Efficacy of Centanafadine SR as a Potential Smoking Cessation Treatment
Phase: PHASE2
Conditions: Smoking Cessation
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

 
Main Office • 7240 ACC Blvd • Raleigh, NC 27617 
 
 
 
Clinical Study Protocol 
 
 
Study Title: 
Efficacy of Centanafadine SR as a potential smoking 
cessation treatment 
Protocol Number:  
Protocol # 405-201-00055 
Compound:  
 
Centanafadine Sustained release Tablets (EB-1020) 
IND Number: 
155242 
Sponsor: 
Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
2440 Research Boulevard 
Rockville, Maryland 20850, United States 
IRE Contact: 
Rose Research Center 
 
Email: 
 
Phone: 
 
Version Number:   
Version 3.0 – Amendment 1 
Version Date:  
 
August 16, 2021 
Principal Investigator: 
 
Medical Supervision:  
 
Protocol Authors: 
 
 
 
  
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of United States law. No part of this document may be publicly 
disclosed without the written consent of the Rose Research Center, LLC. 
 
Synopsis Clinical Study Report 405-201-00055
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 
Appendix ....................................................................................................................................................... 6 
Figures ........................................................................................................................................................... 7 
Tables ............................................................................................................................................................ 7 
Explanation of Terms .................................................................................................................................... 7 
Abbreviations ................................................................................................................................................ 8 
Summary of Changes .................................................................................................................................. 11 
Amendment 1 – Protocol Version 3.0 – 16 Aug 2021 ............................................................................. 11 
Synopsis ...................................................................................................................................................... 12 
 
Introduction ........................................................................................................................................ 14 
1.1 
Background ................................................................................................................................. 14 
1.2 
Study Rationale ........................................................................................................................... 15 
 
Study Objectives and Endpoints ......................................................................................................... 15 
2.1 
Primary Objective: Smoking Abstinence ..................................................................................... 15 
2.1.1 
Endpoints ............................................................................................................................ 15 
2.2 
Secondary Objective: Reduction in Incidence of Nausea ........................................................... 15 
2.2.1 
Endpoint .............................................................................................................................. 15 
 
Investigational Plan ............................................................................................................................. 16 
3.1 
Overall Study Design and Plan .................................................................................................... 16 
3.2 
Study and Session Durations ....................................................................................................... 16 
 
Participant Involvement ...................................................................................................................... 16 
4.1 
Point of Enrollment ..................................................................................................................... 16 
4.2 
Inclusion Criteria ......................................................................................................................... 17 
4.3 
Exclusion Criteria ......................................................................................................................... 17 
4.3.1 
Participants of Childbearing Potential (CBP) ....................................................................... 18 
4.4 
Recruitment Strategies ............................................................................................................... 19 
4.4.1 
Pre-Screening ...................................................................................................................... 19 
4.5 
Participant Retention in the Study .............................................................................................. 19 
4.6 
Discontinuation of Participants from Study ................................................................................ 19 
4.7 
Lost to Follow-up ........................................................................................................................ 20 
4.8 
Violation of Inclusion/Exclusion Criteria ..................................................................................... 20 
4.9 
Session and Response Windows ................................................................................................. 20 
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4.9.1 
V2 Session Window ............................................................................................................. 20 
4.9.2 
V3 Session Window ............................................................................................................. 20 
4.9.3 
All other visit Windows ....................................................................................................... 20 
4.9.4 
Daily Message Response Window ...................................................................................... 20 
 
Investigational Medicinal Product (IMP) ............................................................................................ 20 
5.1 
Centanafadine SR (EB-1020) ....................................................................................................... 20 
5.1.1 
Packaging and Labeling ....................................................................................................... 21 
5.2 
Dosing Regimen .......................................................................................................................... 21 
5.2.1 
Dosing Rationale ................................................................................................................. 21 
5.2.2 
Dose Adjustment Procedures ............................................................................................. 21 
5.3 
Storage and Accountability ......................................................................................................... 21 
5.3.1 
Storage ................................................................................................................................ 21 
5.3.2 
Accountability ..................................................................................................................... 22 
5.3.3 
Destruction .......................................................................................................................... 22 
5.4 
Product Quality Complaints ........................................................................................................ 22 
5.4.1 
Eliciting and Reporting a PQC ............................................................................................. 22 
5.4.2 
Information Required for Reporting Purposes ................................................................... 22 
5.4.3 
Return Process for Complaint Sample ................................................................................ 23 
5.4.4 
Assessment and Evaluation ................................................................................................ 23 
 
Study Procedures and Activities ......................................................................................................... 23 
6.1 
Informed Consent and Guidance ................................................................................................ 23 
6.2 
Virtual Screening Procedures ...................................................................................................... 23 
6.3 
Sampling for Future Biospecimen Research (FBR) ...................................................................... 24 
6.4 
Samplings for Pharmacokinetics (PK).......................................................................................... 24 
6.5 
Safety Evaluations and Other Assessments ................................................................................ 24 
6.5.1 
Clinical Chemistry ................................................................................................................ 25 
6.5.2 
Hematology ......................................................................................................................... 25 
6.5.3 
Serum Pregnancy Test......................................................................................................... 25 
6.5.4 
Urinalysis ............................................................................................................................. 25 
6.5.5 
Urine Drug Screen ............................................................................................................... 25 
6.5.6 
Urine Pregnancy Test .......................................................................................................... 26 
6.5.7 
Electrocardiogram (ECG) ..................................................................................................... 26 
6.5.8 
Vital Signs ............................................................................................................................ 26 
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4.1 Protocol and Protocol Amendments
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6.5.9 
Physical Examination ........................................................................................................... 26 
6.5.10 
Expired Air CO Breath Test .................................................................................................. 26 
6.5.11 
Medical History and Concomitant Disease ......................................................................... 26 
6.5.12 
Prior and Concomitant Medication ..................................................................................... 27 
6.5.13 
Body Height and Body Weight ............................................................................................ 27 
6.5.14 
Demographics ..................................................................................................................... 27 
6.5.15 
AE/SAE Reporting ................................................................................................................ 27 
6.5.16 
Questionnaires .................................................................................................................... 27 
6.6 
Visit Procedures .......................................................................................................................... 29 
6.6.1 
Screening (V1) ..................................................................................................................... 29 
6.6.2 
Baseline (V2) – Day -1 ......................................................................................................... 29 
6.6.3 
Day before Quit Day (V3) – 1 week on IMP ........................................................................ 30 
6.6.4 
Visit 4 (V4) – 3 weeks on IMP .............................................................................................. 31 
6.6.5 
Visit 5 (V5) – 5 weeks on IMP .............................................................................................. 31 
6.6.6 
Final Study Visit (V6) – 7 weeks on IMP .............................................................................. 32 
6.6.7 
Telephone Contact .............................................................................................................. 33 
6.6.8 
Safety Follow-Up ................................................................................................................. 33 
6.7 
Daily Messaging .......................................................................................................................... 33 
6.7.1 
Daily Message (after screening, prior to V2) ...................................................................... 33 
6.7.2 
Daily Message (Visit 2 through V6) ..................................................................................... 33 
6.8 
Schedule of Events ...................................................................................................................... 34 
 
Risk / Benefit Information ................................................................................................................... 35 
7.1 
Potential Benefits ........................................................................................................................ 35 
7.2 
Importance of Knowledge to be Gained ..................................................................................... 35 
7.3 
Potential Risks ............................................................................................................................. 35 
7.3.1 
Centanafadine SR ................................................................................................................ 35 
7.3.2 
Tobacco Withdrawal ........................................................................................................... 35 
7.3.3 
Blood Draw .......................................................................................................................... 35 
7.4 
Concomitant Medications ........................................................................................................... 35 
7.5 
Protection Against Risks .............................................................................................................. 36 
7.5.1 
Blood Pressure Monitoring ................................................................................................. 36 
 
Quality Control and Quality Assurance ............................................................................................... 36 
8.1 
Monitoring Activities ................................................................................................................... 36 
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4.1 Protocol and Protocol Amendments
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8.1.1 
Site Initiation Visit (SIV) ....................................................................................................... 36 
8.1.2 
Interim Monitoring Visits (IMVs) ........................................................................................ 37 
8.1.3 
Close-Out Visit (COV) .......................................................................................................... 37 
8.2 
Training of Staff ........................................................................................................................... 37 
8.3 
Audits and Inspections ................................................................................................................ 37 
 
Adverse Events .................................................................................................................................... 37 
9.1 
Definitions ................................................................................................................................... 37 
9.1.1 
Adverse Event (AE) .............................................................................................................. 37 
9.1.2 
Serious Adverse Event (SAE) ............................................................................................... 38 
9.1.3 
Nonserious Adverse Event .................................................................................................. 38 
9.1.4 
Immediately Reportable Event (IRE) ................................................................................... 38 
9.1.5 
Psychiatric Adverse Events.................................................................................................. 38 
9.1.6 
Changes in Clinical Laboratory Test Values ......................................................................... 39 
9.2 
Collection of Safety Events from Participants ............................................................................. 39 
9.2.1 
Period of Collection ............................................................................................................. 39 
9.3 
Assessment of Adverse Events ................................................................................................... 40 
9.3.1 
Severity of Adverse Events .................................................................................................. 40 
9.3.2 
IMP Causality ....................................................................................................................... 40 
9.4 
Immediately Reportable Events .................................................................................................. 40 
9.5 
Adverse Events of Special Interest .............................................................................................. 40 
9.6 
Abuse Potential Monitoring Plan ................................................................................................ 41 
9.7 
Potential Serious Hepatotoxicity ................................................................................................ 41 
9.8 
Pregnancy after Enrollment ........................................................................................................ 41 
9.9 
Follow-up of Non-serious Adverse Events .................................................................................. 42 
9.10 
Follow-up of Serious Adverse Events and Immediately Reportable Events ............................... 42 
9.11 
Follow-up and Reporting of Serious Adverse Events and Immediately Reportable Events 
Occurring after Last Scheduled Contact ................................................................................................. 43 
 Data Management .............................................................................................................................. 43 
10.1 
Data Collection Procedures ......................................................................................................... 43 
10.2 
Protocol Deviations / Noncompliance ........................................................................................ 43 
10.3 
Data Capture ............................................................................................................................... 43 
10.3.1 
Pre-screening Data .............................................................................................................. 44 
10.3.2 
At-home Data Collection ..................................................................................................... 44 
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4.1 Protocol and Protocol Amendments
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10.3.3 
Electronic Data Capture System.......................................................................................... 44 
10.4 
Missing Data ................................................................................................................................ 44 
10.5 
Data Handling .............................................................................................................................. 44 
10.6 
Data Validation............................................................................................................................ 44 
10.7 
Database Lock ............................................................................................................................. 44 
 Planned Statistical Methods ............................................................................................................... 45 
11.1 
Sample Size Estimation ............................................................................................................... 45 
11.2 
Statistical Methods ..................................................................................................................... 45 
11.3 
Outcomes .................................................................................................................................... 45 
11.3.1 
Smoking Abstinence ............................................................................................................ 45 
11.3.2 
Incidence of Nausea ............................................................................................................ 45 
 Ethics and Regulations ........................................................................................................................ 46 
12.1 
IRB Approval ................................................................................................................................ 46 
12.2 
Investigational New Drug Application ........................................................................................ 46 
12.3 
GCP and Regulatory Requirements ............................................................................................. 46 
12.4 
Participant Information and Consent ......................................................................................... 46 
12.5 
Amendment to Informed Consent Form .................................................................................... 46 
 Administrative Considerations ............................................................................................................ 47 
13.1 
Participant Confidentiality .......................................................................................................... 47 
13.2 
Records Retention ....................................................................................................................... 47 
13.2.1 
File Management at the Trial Site ....................................................................................... 47 
13.2.2 
Records Retention at the Trial Site ..................................................................................... 47 
13.3 
Publication Authorship Requirements ........................................................................................ 47 
 References .......................................................................................................................................... 49 
 
APPENDIX 
Appendix 1 - Columbia-Suicide Severity Rating Scale (C-SSRS), "Screening" and "Since Last Visit" ........... 52 
Appendix 2 – Fagerström Test for Nicotine Dependence (FTND) ............................................................... 58 
Appendix 3 – Smoking History .................................................................................................................... 59 
Appendix 4 – Other Nicotine Use Questionnaire........................................................................................ 60 
Appendix 5 – Modified Cigarette Evaluation Questionnaire – Extended (mCEQE) .................................... 61 
Appendix 6 – Reasons to Smoke ................................................................................................................. 63 
Appendix 7 – Shiffman Jarvik Withdrawal Scale ......................................................................................... 64 
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4.1 Protocol and Protocol Amendments
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Appendix 8 – Minnesota Nicotine Withdrawal Scale ................................................................................. 66 
FIGURES 
Figure 1 - Overall Study Design and Plan, 7-Week Treatment Period ........................................................ 16 
 
TABLES 
Table 1 - Clinical Chemistry ......................................................................................................................... 25 
Table 2 - Hematology .................................................................................................................................. 25 
Table 3 - Serum Pregnancy ......................................................................................................................... 25 
Table 4 - Urinalysis ...................................................................................................................................... 25 
Table 5 - Drug Screening ............................................................................................................................. 26 
Table 6 - Schedule of Event ......................................................................................................................... 34 
EXPLANATION OF TERMS 
The following special terms are used in this protocol:  
Baseline Visit 
The baseline visit for this study is defined a V2. 
Baseline Value 
The baseline value is defined as the value at V2 unless otherwise specified. 
End of Study 
The end of study (EOS) for a subject is defined as the date of safety follow-up 
or the date of early termination of the subject.  
Combustible cigarette 
The term ‘combustible cigarette’ (CC) refers to commercially available, 
combustible cigarettes and excludes hand-rolled cigarettes, cigars, pipes, 
bidis, and other nicotine containing products. 
Volunteer 
A volunteer is an individual who has expressed interest in participating in a 
clinical research study. 
Candidate 
Individuals who completed a pre-screening evaluation with a member of the 
Rose Research Center recruitment team. They have been deemed as pre-
qualified to come in for a physical screening visit to determine further 
eligibility. 
Participant 
A volunteer who has signed the study consent form. Once an individual signs 
the study consent form and receives a participant number, they are 
considered a Participant. The term “Subject” can and has historically been 
used interchangeably with Participant but for the purposes of 
communication, RRC has adopted the term participant as a global term for 
this status. 
 
 
 
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ABBREVIATIONS 
5-HT 
Serotonin 
ADHD 
Attention-deficit/hyperactivity disorder 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
APMP 
Abuse Potential Monitoring Process 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BL 
Baseline 
BMI 
Body mass index 
BUN 
Urea nitrogen 
CBP 
Childbearing potential 
CC 
Combustible cigarette 
CFR 
Code of Federal Regulations 
CO 
Carbon monoxide 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DA 
Dopamine 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of Study 
FBR 
Future biospecimen research 
FDA 
Food and Drug Administration  
ESAM 
Events Subject to Additional Monitoring 
FTND 
Fagerström test for nicotine dependence 
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GCP 
Good Clinical Practice 
HBA1c 
Hemoglobin A1c 
HCG 
Human chorionic gonadotropin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRE 
Immediately Reportable Event 
kg 
Kilograms 
Lbs 
pounds 
MAOI 
Monoamine Oxidase Inhibitor 
mCEQ 
Modified Cigarette Evaluation Questionnaire. 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mg 
Milligram 
MHI 
Medication handling irregularity 
mL 
Milliliter 
MNWS 
Minnesota Nicotine Withdrawal Scale 
NE 
Norepinephrine 
OPDC 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
PPM 
Parts per million 
PQC 
Product Quality Complain 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
RCT 
Randomized Control Trial 
RNA 
Ribonucleic acid 
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RRC 
Rose Research Center, LLC. 
SaaS 
Software-as-a-Service 
SAE 
Serious adverse event 
SMS 
Short Message Service 
SNRI 
Selective Norepinephrine Reuptake Inhibitor 
SOP 
Standard operating procedure 
SR 
Sustained Release 
SSL 
Secure Sockets Layer 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TCA 
Tricyclic Antidepressant 
TDD 
Total daily dose 
TLS 
Transport Layer Security 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
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SUMMARY OF CHANGES 
AMENDMENT 1 – PROTOCOL VERSION 3.0 – 16 AUG 2021 
• 
Clarification of “smoking cessation treatments” in Exclusion #14. 
• 
Clarification of exclusionary medications in Exclusion #7. 
• 
The PHQ-9 has been replaced with the C-SSRS based on recommendations from the FDA. 
Section 9.1.5 Psychiatric Adverse Events was added. 
• 
Additional questionnaire added to assess use of other forms of nicotine between study visits. 
• 
Clarification of laboratory tests ordered to properly characterize non-traumatic lesions. (Section 
9.5 – Adverse Events of Special Interest) 
 
 
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SYNOPSIS 
SPONSOR 
Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
2440 Research Boulevard 
Rockville, Maryland 20850, United States 
INVESTIGATIONAL PRODUCT 
Centanafadine Sustained release Tablets (EB-1020) 
STUDY TITLE 
Efficacy of centanafadine SR as a potential smoking cessation treatment  
PROTOCOL NUMBER 
405-201-00055 
EXECUTIVE SUMMARY 
This single-group, open-label study of 50 subjects will explore the potential of centanafadine in 
promoting smoking abstinence in adult smokers seeking to quit. The efficacy and tolerability of 
centanafadine at a dose of 400 mg total daily dose (TDD) (200 mg twice daily [BID]) approximately 4 to 6 
hours apart (during a 7-week treatment period) will be compared with a benchmark of abstinence based 
on historical data from clinical trials of varenicline, viewed as the most efficacious pharmacotherapy 
currently approved by the FDA. 
OBJECTIVES AND ENDPOINTS 
The primary endpoint is the four-week continuous abstinence rate of subjects with the treatment of 
centanafadine during weeks 4-7. A participant is considered abstinent from combustible cigarettes if he 
or she self-reports tobacco abstinence (no cigarette smoking, not even a puff) assessed by responses to 
daily messages throughout the period and has an exhaled carbon monoxide (CO) level of less than 5 
ppm using the Vitalograph BreathCO monitor in the office at Visit 5 and Visit 6. 
A secondary objective will be to determine if centanafadine yields equivalent efficacy to that of 
varenicline, with a significant reduction in the incidence of nausea the most prevalent side effect 
reported following varenicline treatment. Incidence rate of nausea is assessed by self-reported side 
effects collected via an open-ended question at each study visit. 
STUDY DESIGN 
This single-group, small-scale, open-label study (N= 50) will evaluate centanafadine SR (400 TDD) as a 
potential smoking cessation treatment. Participants enrolled in the study will be given centanafadine SR 
at a dose of 400 mg TDD (200 mg BID) approximately 4 to 6 hours apart for seven weeks.  
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The study will consist of up to a 28-day screening period, a baseline visit, a 7-week treatment period, 
and a 7-day safety follow-up period. 
  
DOSING RATIONALE 
The 400 mg TDD of centanafadine SR oral tablets (200 mg BID) will be evaluated in this study.  This dose 
was found to produce a significant blockade (>10%) of transporters for serotonin, dopamine, and 
norepinephrine as well as alleviating symptoms of inattention and hyperactivity/impulsivity in patients 
with ADHD, without inducing a high incidence of nausea and headache that occur with doses as high as 
800 mg.1   
SAMPLE SIZE ESTIMATION 
Given the conditional logic of the phase one analyses, Monte Carlo simulations based on a sample size 
of 50 were conducted to determine the significance thresholds for the binomial tests so that the overall 
Type I error rate across all tests would be 10% (9.87% of 100,000 simulated datasets), assuming the null 
hypothesis that centanafadine yields a four-week continuous smoking abstinence rate of 50% and an 
overall incidence of nausea of 30%. The power of the phase one analyses (probability of moving to 
phase two) was also determined by Monte Carlo simulations for three scenarios.  In the first scenario, 
the treatment has a higher four-week continuous abstinence rate at 6 weeks post target quit date (65%) 
than varenicline, but an equivalent rate of nausea (30%). Power under this scenario is about 74%. In the 
second scenario, the treatment has the same four-week continuous abstinence rate at 6 weeks post 
target quit date as varenicline (50%) but has a lower nausea rate (15%). Power under this scenario is 
about 76%. Last, if the treatment generates both a higher four-week continuous abstinence rate at 6 
weeks post target quit date (65%) and a lower rate of nausea (15%) then power is about 94%. 
STATISTICAL METHODS 
The estimation of the four-week continuous smoking abstinence rate at 6 weeks post target quit date is 
around 50% and 30% of treated individuals experiencing nausea from varenicline treatment based on 
the historical studies.2 The smoking abstinence rate during weeks 4-7 will be calculated with 90% 
binomial confidence intervals, and the incidence rate of nausea will be tabulated, which will be 
compared with the thresholds established for efficacy and tolerability.  
 
SCR
Screening 
Period
WK1
WK4
V1
V2
V6
(± 3 days)
(+ 2 days)
7-Week Treatment Period
V4
(± 3 days)
V5
(± 3 days)
V3
Phone 
Call
1 Week IMP
Baseline
(+ 3 days)
Day -1
Day 1 
First dose IMP
3 Weeks IMP
5 Weeks IMP
7 Weeks IMP
Last dose IMP
7-Day Safety 
Follow-up
Target 
Quit Day
WK8
WK7
WK2
WK3
WK5
WK6
Centanafadine SR 400 mg TDD
(200 mg BID)
Centanafadine 
SR 400 mg TDD
(200 mg BID)
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 INTRODUCTION 
1.1 BACKGROUND 
Cigarette smoking remains the leading cause of preventable death in the United States, and is one of the 
leading causes of preventable morbidity and mortality.3,4 An estimated 540,000 smokers die each year 
from smoking-related diseases.5 Existing treatments for tobacco cessation yield, on average, less than 
25% long-term abstinence rates, with many of the cessation failures occurring within the first month of 
abstinence.6 There is an urgent need to develop new therapies for smoking cessation.7 Current 
pharmacological approaches  are efficacious for smoking cessation, but continue to have poor long-term 
abstinence rates, with potentially concerning adverse events. 
There are currently seven Food and Drug Administration (FDA)-approved smoking cessation 
medications, which fall into three main categories: nicotine replacement therapy (NRT) including 
nicotine patch, gum, lozenge, inhaler, and nasal spray; varenicline (Chantix); and bupropion 
(Zyban/Wellbutrin). Among US smokers, 29.1% use NRT when attempting to quit smoking whereas only 
7.9% use varenicline and 2.4% use bupropion.8,9 Two other medications that show some efficacy, 
clonidine and nortryptyline, are not FDA approved, and account for less than 1% of smoking cessation 
treatment.10 None of the current treatments yields sustained abstinence rates of over 25% at one year, 
but varenicline is the most efficacious. Varenicline is a full agonist on α7-nicotinic acetylcholine 
receptors (nAChRs) and a partial agonist on the α4β2, α3β4, and α6β2 subtypes.2,11,12 Smoking 
abstinence rates at weeks 9-12 in two Phase III trials of varenicline were nearly identical at 44%. Given 
that four-week continuous abstinence at weeks 4-7 will be taken to be the primary abstinence outcome 
in the present study, and modeling relapse curves over the initial weeks of abstinence suggests that 
abstinence rates are ~5% higher at 6 weeks than at 12 weeks after the target quit-smoking date,13 in this 
study a slightly higher rate of 50% abstinence will be taken to be the benchmark criterion to meet or 
exceed. Common adverse events associated with varenicline include nausea, insomnia, abnormal 
dreams, headaches, and nasopharyngitis.14 The most common adverse reaction reported is nausea, with 
30-40% of participants in randomized control trials reporting mild to moderate levels of nausea.15 
Discontinuation/drop-out rates of nearly 10% have been noted during clinical trials due to these adverse 
effects.16 In real-world settings, discontinuation of varenicline treatment may be as high as 57%.8 
Nicotine inhaled from cigarette smoke reaches the brain rapidly17 and acts on nicotinic acetylcholine 
receptors to release several neurotransmitters involved in arousal, attention and mood regulation. 
Among these are the monoamines dopamine, norepinephrine and serotonin.18,19 When dependent 
smokers abstain from smoking, nicotine withdrawal symptoms are experienced, including difficulty 
concentrating, irritability, and depressed mood,20 which are thought to be due in part to a deficit in 
monoamine neurotransmitter activity. Centanafadine is a triple monoamine transporter inhibitor that 
acts to block re-uptake of norepinephrine, dopamine and serotonin (half-maximal inhibitory 
concentration [IC50] 6 nM), dopamine (IC50 38 nM), and serotonin (IC50 83 nM),21 and thus may 
counteract the withdrawal-induced deficit in these neurotransmitters accompanying smoking cessation. 
Indeed, bupropion, which is an efficacious smoking cessation treatment, is thought to exert its 
therapeutic actions by inhibiting re-uptake of dopamine and norepinephrine.
 
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 Additionally, smoking relapse is 
hypothesized to result in part from impulsivity, which has been shown to be reduced by centanafadine 
treatment.1 
1.2 STUDY RATIONALE 
Smokers that go through nicotine withdrawal often experience difficulty concentrating, hypoarousal, 
and negative mood, which could be alleviated by centanafadine’s effect in enhancing monoamine 
neurotransmitter activity.  
This trial will explore the potential of centanafadine in promoting smoking abstinence in adult smokers 
seeking to quit. The efficacy and tolerability of centanafadine at a dose of 400 mg per day will be 
compared with a benchmark of abstinence based on historical data from clinical trials of varenicline, 
viewed as the most efficacious pharmacotherapy currently approved by the FDA.  
This single-group, open-label study of 50 participants will evaluate oral administration of centanafadine 
sustained-release tablets (EB-1020), to help smokers abstain from smoking combustible cigarettes 
during a 7-week study period.  
 STUDY OBJECTIVES AND ENDPOINTS 
2.1 PRIMARY OBJECTIVE: SMOKING ABSTINENCE 
The primary objective will be to determine whether centanafadine yields a superior four-week 
continuous smoking abstinence rate compared to varenicline during weeks 4-7. Abstinence will be 
defined as self-report of no cigarette smoking (not even a puff), confirmed by an expired air CO reading 
of less than 5 ppm at week 7. 
2.1.1 
Endpoints 
• Self-report of no cigarette smoking (not even a puff), assessed by responses on daily 
messages.  
• Expired air CO reading of less than 5 ppm, assessed in office using the Vitalograph BreathCO 
monitor. 
2.2 SECONDARY OBJECTIVE: REDUCTION IN INCIDENCE OF NAUSEA 
A secondary objective will be to determine if centanafadine yields equivalent efficacy to that of 
varenicline), with a significant reduction in the incidence of nausea, the most prevalent side effect 
reported following varenicline treatment. 
2.2.1 
Endpoint 
Self-report of side effects assessed by open-ended question at each study visit. 
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 INVESTIGATIONAL PLAN 
3.1 OVERALL STUDY DESIGN AND PLAN 
This single-group, small-scale, open-label, phase 2 study (N= 50) will evaluate centanafadine as a 
potential smoking cessation treatment. The dose of centanafadine SR that will be evaluated in this trial 
will be 400 mg TDD (200 mg BID) approximately 4 to 6 hours apart for seven weeks. 
The study will consist of a 14-day screening period, a baseline visit, a 7-week treatment period, and a 7-
day safety follow-up period. Participants will visit the study center a total of six times, including a 
screening visit (V1), baseline visit (V2), a visit one week (+ 3 days) after starting the study drug (V3), 
three weeks (± 3 days) after starting the study drug (V4), five weeks (± 3 days) after starting the study 
drug (V5), and seven weeks (± 3 days) after starting the study drug (V6). All participants will be 
requested to participate in a 7-day safety follow up period, which will consist of telephone contact seven 
days (+2 days) after the last dose of investigational product. 
  
Figure 1 - Overall Study Design and Plan, 7-Week Treatment Period 
3.2 STUDY AND SESSION DURATIONS 
The total duration for a participant will be approximately 10 weeks. The Screening Session (Visit 1) will 
last approximately 2 ½ to 3 hours. The other study sessions will last approximately 1 to 1 ½ hours. 
 PARTICIPANT INVOLVEMENT 
The study population will include fifty (50) cigarette smoking adults, between 21 and 65 years of age, 
inclusive, with no restriction on gender, race and ethnicities, or social-economic status, who have 
smoked an average of at least 10 commercially available cigarettes per day for the last 12 months. 
4.1 POINT OF ENROLLMENT 
Participants will be enrolled at V2, after all safety laboratory results have been received and reviewed by 
the medical staff (MD or PA).  
SCR
Day 1 
First dose IMP
3 Weeks IMP
5 Weeks IMP
7 Weeks IMP
Last dose IMP
V1
V6
(± 3 days)
(+ 2 days)
7-Week Treatment Period
V4
(± 3 days)
V5
(± 3 days)
V3
Phone 
Call
1 Week IMP
V2
Baseline
(+ 3 days)
Day -1
7-Day Safety 
Follow-up
Target 
Quit Day
WK8
WK7
WK2
WK3
WK5
WK6
Centanafadine SR 400 mg TDD
(200 mg BID)
Centanafadine 
SR 400 mg TDD
(200 mg BID)
Screening 
Period
WK1
WK4
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4.2 INCLUSION CRITERIA 
Inclusion Criteria 
1.  
Has signed the ICF and is able to read and understand the information provided in the ICF.  
2.  
Smokers 21 to 65 years of age (inclusive) at screening. 
3.  
Smokes an average of at least 10 commercially available cigarettes per day for the last 12 months. 
4.  
Has an expired air CO reading of at least 10 ppm at screening. 
5.  
At screening, express a desire to quit smoking within the next 30 days. 
6.  
BMI of 18 to 40 kg/m2, inclusive at screening. 
7.  
Willing and able to comply with the requirements of the study. 
8.  
Owns a smart phone with text message and data capabilities compatible with necessary surveys. 
4.3 EXCLUSION CRITERIA 
Exclusion Criteria 
1. 
 
Participants of childbearing potential (CBP) who are breast-feeding and/or have a positive pregnancy 
test result. 
2. 
 
Participant presenting with, or having a history of, uncontrolled hypertension (systolic blood pressure > 
150 mmHg or diastolic blood pressure > 95 mmHg) or symptomatic hypotension. 
3. 
 
Participants with known ischemic heart disease or history of myocardial infarction, congestive heart 
failure (whether controlled or uncontrolled), angioplasty, stenting, coronary artery bypass surgery, or 
other serious cardiac problems that would place him/her at increased vulnerability to the 
sympathomimetic effects of a stimulant medication. 
4. 
 
History of seizures (after the age of 17 years). 
5. 
 
Participants of CBP or sexually active participants unless they 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 
Investigation Medicinal Product (IMP) for participants of CBP, and 30 days after the last dose of IMP for 
participants with partners who are of CBP. Unless the participant is sterile (i.e., participants who have 
had a bilateral oophorectomy or hysterectomy or who have been postmenopausal for at least 12 
consecutive months; or participants 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. Participants who do not agree to refrain from donating 
sperm from screening through 30 days after the last dose of IMP. 
6. 
 
Participant has a history of dermatologic adverse reactions secondary to any drug exposure or any 
active/uncontrolled dermatologic disease. 
7. 
 
Currently taking antidepressants (e.g., SSRI’s SNRI’s, TCA’s or MAOI’s), antipsychotics (such as 
butyrophenones, thioxanthines, atypical antipsychotics or other heterocyclics), benzodiazepines, 
hypnotics, or medications that prolong QTc. MAOI’s taken within 30 days of screening. 
8. 
 
Screening (Visit 1) or Baseline (Visit 2) C-SSRS score greater than 0 (any answer “Yes”) for the SUICIDAL 
IDEATION section or greater than 0 for the SUICIDAL BEHAVIOR section (any answer “Yes”)  
9. 
 
Substance use disorder within 12 months prior to screening. 
10.  
Participants that have a positive alcohol test (via breathalyzer or blood), a positive drug screen for illicit 
drugs (Table 6.3.5) at screening or baseline.  
NOTE: Participants who test positive for marijuana at screening may be enrolled if they have no 
evidence of a substance use disorder and if they agree to refrain from use for the duration of the trial. 
11.  
Any participant who has any other medical or physical condition(s) that, in the opinion of the 
investigator, may prevent the participant from completing the trial or would go against the 
participant’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. 
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Exclusion Criteria 
12.  
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, participants 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 participant or the interpretation of the trial results. 
13.  
Participants with a history of prior exposure to centanafadine. 
14.  
Use of smokeless tobacco (chewing tobacco, snuff), cigars (except for “Black & Mild” cigars or 
Cigarillos), pipes, hookah, e-cigarettes, nicotine replacement therapy or other smoking cessation 
treatments (e.g., bupropion as Zyban, or varenicline) within 14 days of screening. 
15.  
Participants who participated in a clinical trial and were exposed to interventional trial medication 
within the last 30 days prior to screening or who participated 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. 
4.3.1 Participants of Childbearing Potential (CBP) 
Participants of CBP are defined as participants for whom menstruation has started and who are not 
documented as sterile (ie, have had a bilateral oophorectomy and/or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months). 
For participants of CBP and for participants who are sexually active, there must be a documented 
agreement that the participant and/or their partner will take effective measures (i.e., double-barrier 
method) to prevent pregnancy during the course of the trial and for 30 days after the last dose of IMP. 
Unless the participant is sterile (i.e., females who have had a bilateral oophorectomy and/or 
hysterectomy or who have been postmenopausal for at least 12 consecutive months; or males who have 
had a bilateral orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth control 
injection, birth control implant, birth control patch, condom with spermicide, or sponge with 
spermicide. Any single method of birth control, including vasectomy and tubal ligation, may fail, leading 
to pregnancy. The contraceptive method will be documented at each trial visit. Male participants must 
also agree not to donate sperm from screening through 30 days after the last dose of IMP. 
Before trial enrollment, participants of CBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The participant 
must sign an informed consent form stating that the above-mentioned risk factors and the 
consequences were discussed with her. 
A serum pregnancy test (screening visit only) or urine pregnancy test (all other visits) for human 
chorionic gonadotropin will be performed on participants who have the potential to become pregnant. 
If a urine test is performed and is positive, the investigator will follow up with a confirmatory serum test. 
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4.4 RECRUITMENT STRATEGIES 
 
 
 
 
 
 
 
 
 
 
 
  
4.4.1 
Pre-Screening 
Pre-screening will be completed prior to V1 for all participants. Participants will be provided with a set of 
IRB approved questions directly related to the inclusion and exclusion criteria. Based upon the outcome 
of these questions, potential participants may be scheduled for a screening visit (V1). 
4.5 PARTICIPANT RETENTION IN THE STUDY 
All candidates who schedule a screening visit (V1) will receive a series of email, text, and telephone 
reminders; participants are also permitted through these communications to confirm, cancel, or 
reschedule all their appointments. 
4.6 DISCONTINUATION OF PARTICIPANTS FROM STUDY 
Discontinued participants will include both participants who withdraw from the study (participant’s 
decision) or participants who are discontinued from the study (following Investigator’s decision). A 
participant can only be discontinued from the study after the IMP is dispensed to them. Participants that 
are not dispensed the IMP are considered screen failures. 
Participants will be informed that they are free to withdraw from the study at any time. Participants 
should be questioned for the reason of premature withdrawal from the study, although they are not 
obliged to disclose it.  
Participants discontinued from the study cannot re-enter the study.  
Participants will be discontinued from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Any adverse effect or condition that would jeopardize continued safe study participation. 
• Discontinuation is considered to be in the best interest for the participant or for other 
participants participating in the study, as judged by the Investigator or designee. 
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Participants may be discontinued from the study for any of the following reasons based on the judgment 
of the Investigator: 
• No-show to appointments and unable to reschedule within the visit window. 
• The misuse or abuse of study related equipment. 
• Potential loss of the participant’s data validity. 
• Unwilling or unable to comply with study procedures. 
4.7 LOST TO FOLLOW-UP 
For participants lost to follow-up, three attempts to contact the participant (including written 
correspondence and/or phone calls) will be made and documented in the source documents. The date 
of the last contact (e.g., last visit, last phone call) will be recorded in the source document. When the PI 
(or designee) declares a participant is lost to follow-up, the lost to follow-up date will be recorded and 
will correspond to the date of the End of Study (EOS) of the participant. 
4.8 VIOLATION OF INCLUSION/EXCLUSION CRITERIA 
Participants who, after signing the ICF, do not meet the inclusion and exclusion criteria will be 
considered screen failures. Re-screening for the study is not permitted. 
4.9 SESSION AND RESPONSE WINDOWS 
4.9.1 
V2 Session Window 
Participants may attend V2 up to 28 calendar days post Screening Session (V1). 
4.9.2 
V3 Session Window 
Participants may attend V3 up to 3 calendar days post scheduled visit. 
4.9.3 
All other visit Windows 
Participants may attend sessions up to three calendar days pre or post the scheduled visit. 
4.9.4 
Daily Message Response Window 
The survey response window will be open until the next survey response message is sent.  
 INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
5.1 CENTANAFADINE SR (EB-1020) 
Centanafadine is an investigational drug that has inhibitory activity at norepinephrine (NE), dopamine 
(DA), and serotonin (5-HT) reuptake transporters.1 It has the highest activity for inhibition for 
norepinephrine reuptake (half-maximal inhibitory concentration [IC50] 6 nM), but also inhibits dopamine 
(IC50 38 nM) and serotonin (IC50 83 nM) transporter reuptake.23  
Two phase 2 trials showed that the SR version of centanafadine was safe and well tolerated in adults 
with attention deficit hyperactivity disorder (ADHD). The first study administered up to a TDD of 500 mg 
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(split into twice daily dosing) for two weeks.21 The second study compared TDDs of 400 mg, 600 mg, and 
800 mg in terms of safety and efficacy for reducing ADHD symptoms. Both studies concluded that 
centanafadine SR 400 mg TDD (200 mg BID) was effective and well tolerated and did not result in sleep 
disturbances, and there were no signs of abuse or diversion.21 The most common adverse events 
reported were headache (20%, placebo = 9%), decreased appetite (16%, placebo = 0%), and upper 
respiratory tract infection (16%, placebo = 11%).21 
5.1.1 
Packaging and Labeling 
Trial medication will be provided to the investigators and the persons designated by the investigator(s) 
or institution(s) by the sponsor or designated agent. Trial medication will be labeled to clearly disclose 
the trial number, sponsor’s name and address, instructions for use, route of administration, and 
appropriate precautionary statements. 
5.2 DOSING REGIMEN 
Centanafadine SR will be administered orally at a 400 mg TDD (200 mg BID) approximately 4 to 6 hours 
apart for a total of seven weeks. Doses of centanafadine SR can be taken without regard to meals and 
should be taken at approximately the same time each day, with the first dose taken in the morning. The 
second dose should be taken 4 to 6 hours after the first dose.  If a subject forgets to take their second 
dose, they can take it up to 7 hours after their first dose; if they remember after 7 hours, they should 
skip the dose and resume dosing the next day. 
5.2.1 
Dosing Rationale 
The 400 mg dose of centanafadine SR will be evaluated in this study.  This dose was found to produce a 
significant blockade (>10%) of transporters for serotonin, dopamine, and norepinephrine as well as 
alleviating symptoms of inattention and hyperactivity/impulsivity in patients with ADHD, without 
inducing a high incidence of nausea and headache that occur with doses as high as 800 mg.1  
5.2.2 
Dose Adjustment Procedures 
The IMP dose may be considered for a one time dose decrease based on tolerability and/or adverse 
events. A one-time dose decrease to 200mg TDD (one pill in am and one pill in pm), based on the clinical 
judgement of the investigator. The subject would remain on the decreased dose (200mg TDD) for the 
remainder of trial participation. If tolerability / AE  does not resolve, post IMP dose-reduction, the 
subject should be considered for trial discontinuation, based on investigator judgement. 
5.3 STORAGE AND ACCOUNTABILITY 
5.3.1 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited to investigators 
and their designees. Neither investigators nor any designees may provide IMP to any participant not 
participating in this protocol. 
The IMP will be stored at controlled room temperature conditions as per the clinical label on the IMP. 
The IMP storage location will be monitored by TempAlert, temperatures will be recorded every 10 
minutes, with alerts triggered (via email, SMS, and phone call) when a temperature falls out-of-
threshold (Severity 3), when a temperature is at risk of going out-of- range (Severity 2), and when a 
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temperature has gone out-of-range (Severity 1). For detailed information about temperature 
monitoring, please refer to RRC’s SOP CLN040 – Facility Temperature Procedures with TempAlert.  
5.3.2 
Accountability 
The investigator or designee will maintain an inventory record of IMP received, dispensed, administered, 
and returned. 
5.3.3 
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. 
5.4 PRODUCT QUALITY COMPLAINTS 
A Product Quality Complaint (PQC) is any written, electronic, or oral communication provided by a 
healthcare professional, clinical trial participant, 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 (e.g., damaged, dirty, crushed, missing product or component, incorrect or 
missing labeling) 
• Product defects (e.g., odor, chipped, broken, damaged, crushed, embossing illegible, under-
filled bottle, over-filled bottle, empty bottle, no safety seal) 
• Loss or theft of product 
5.4.1 
Eliciting and Reporting a PQC 
The investigator or designee must record all PQCs identified through any means from the receipt of the 
IMP from the sponsor or sponsor’s designee, through and including reconciliation and up to destruction, 
including participant dosing. The investigator or designee must notify the sponsor (or sponsor’s 
designee) by e-mail within 24 hours of becoming aware of the PQC according to the procedure outlined 
below: 
Send PQC reporting information to Otsuka Pharmaceutical Development & Commercialization, Inc. 
(OPDC) IMP PQC 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 participant should be reported to the site/investigator, who should then 
follow the reporting mechanism above. 
5.4.2 
Information Required for Reporting Purposes 
• Description of complaint 
• Reporter identification (e.g., investigator, site, etc.) 
• Reporter contact information (e.g., address, phone number, e-mail address) 
• Subject number 
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• 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 
5.4.3 
Return Process for Complaint Sample 
Indicate during the report of the PQC if the complaint sample is available for return.  
If complaint sample is available but not at the clinical site, please instruct participant to bring the 
complaint sample to their next site visit. 
If complaint sample is available for return, the return instructions will be provided by the sponsor. 
It must be documented in the site accountability record that the complaint sample has been forwarded 
to the sponsor for complaint investigation. 
5.4.4 
Assessment and Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
 STUDY PROCEDURES AND ACTIVITIES 
Personnel performing study assessments must have appropriate and documented training. An overview 
of all study assessments is shown in the Schedule of Events. Study personnel will adhere to standard 
operating procedures (SOPs) for all activities. Appropriate medical advice will be provided by qualified 
staff (licensed providers) to the participant in case of any medical findings requiring health care. 
6.1 INFORMED CONSENT AND GUIDANCE 
Prior to any study assessments being performed, the participant will be asked to provide their written 
consent to participate in the study on an informed consent form (ICF). All assessments must start after 
the time of ICF signature by the participant for study participation. 
Designated staff, under the supervision of the Principal Investigator, will obtain informed consent from 
each participant. The person obtaining consent provides the participants with a printed document that 
explains the procedures and risks. Designated staff will answer any questions. A signed copy of the 
informed consent form will be given to each participant. Participants are informed that they may 
withdraw from participation in the study at any time without penalty.  
6.2 VIRTUAL SCREENING PROCEDURES  
To protect against unnecessary risk in the COVID-19 environment, many aspects of screening may be 
conducted virtually. Potential participants will be sent the IRB approved consent form via electronic 
signature. Consenting will take place via virtual meeting where information about the study will be 
explained to potential participants, with adequate time allowed for questions to be answered. Once the 
consent form is signed, the participant will be sent a secure link to complete screening questionnaires. 
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These questionnaires will be reviewed by medical and research staff to determine eligibility prior 
to scheduling the On-Site Visit.   
 
 
 
 
 
 
 
  
6.4 SAMPLINGS FOR PHARMACOKINETICS (PK) 
Blood samples will be taken to determine concentrations of centanafadine and metabolites to assess 
compliance with dosing. The date and time of the sample collection and the date and time of last dose 
of IMP prior to sample collection will be recorded in the CRF. Concentrations of the IMP will be listed in 
the bioanalytical report.  
6.5 SAFETY EVALUATIONS AND OTHER ASSESSMENTS 
Clinical safety evaluations will be performed to ensure that participants meet the requirements of the 
study and to monitor participant safety. An overview of all assessments is provided in the schedule of 
events. 
Urine will be collected, and blood will be drawn from each subject prior to treatment with 
centanafadine. Additional urine and blood samples may be collected for further evaluation of safety as 
warranted by the investigator’s judgment. Reports from the laboratory will be assessed by the 
investigator or qualified designee for clinical significance. 
The results of the clinical chemistry, hematology and urine analysis safety panel will not routinely be 
given to participants to send or be sent to their physician to include in their medical record. However, if 
the participant’s laboratory results are clinically relevant (including positive pregnancy tests), the 
research medical staff will send the participant a copy of the laboratory results. Participants who are 
accepted into the study but need medical follow-up due to minor abnormalities in laboratory results (at 
any session) will also receive a copy of the laboratory results. 
Additional urine and blood samples may be collected for further evaluation of safety as warranted by 
the investigator’s judgment. Reports from the laboratory will be assessed by the investigator or qualified 
designee for clinical significance. 
 
 
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6.5.1 
Clinical Chemistry 
Blood will be collected for Clinical Chemistry tests at the screening visit (V1), V4 and the final study visit 
(V6). 
Clinical Chemistry 
Sodium  
Chloride 
Potassium  
Carbon dioxide 
Urea nitrogen (BUN) 
Creatinine  
Glucose 
Calcium 
Protein, total 
Albumin  
Bilirubin, total 
Alkaline phosphatase (AP) 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Glycosylated Hemoglobin (HbA1c; at screening 
only) 
Gamma-glutamyl transferase (GGT) 
Table 1 - Clinical Chemistry 
6.5.2 
Hematology 
Blood will be collected for Hematology tests at the screening visit (V1), V4 and the final study visit (V6). 
Hematology 
Red blood cell (RBC) count  
WBC count  
Hemoglobin  
Differential white blood cell (WBC) count  
Hematocrit 
Platelet count  
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular hemoglobin (MCH) 
Table 2 - Hematology 
6.5.3 
Serum Pregnancy Test 
Blood will be collected for a serum pregnancy test at the screening visit (V1) for all participants with the 
potential to become pregnant. In case of any positive pregnancy test, the Investigator or designee will 
inform the participant about the risks associated with smoking during pregnancy. 
Serum Pregnancy Test 
Quantitative human chorionic gonadotropin (HCG) test 
Table 3 - Serum Pregnancy 
6.5.4 
Urinalysis 
A urine sample will be collected for Urinalysis at the screening visit (V1) and the final study visit (V6). 
Urinalysis 
pH 
Glucose 
Red blood cell traces 
Specific gravity 
Bilirubin 
Nitrite 
Protein 
WBC Esterase 
Table 4 - Urinalysis 
6.5.5 
Urine Drug Screen 
A urine samples will be collected for a drug screen at the screening visit (V1), V4 and V5. 
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Drug Screening 
Amphetamine 
Cocaine 
THC 
Methamphetamine 
Opiates 
Table 5 - Drug Screening 
6.5.6 
Urine Pregnancy Test 
A urine sample will be collected for a pregnancy test at all study visits (excluding screening). All positive 
urine pregnancy test results will be confirmed by a serum test. Participants with a positive serum 
pregnancy test result during the trial must discontinue treatment and be withdrawn from the trial. The 
Investigator or designee will also inform the participant about the risks associated with smoking during 
pregnancy. For additional information please refer to Section 9.8 Pregnancy after Enrollment.  
6.5.7 
Electrocardiogram (ECG) 
ECG recording will be performed and interpreted at RRC by qualified personnel. A standard 12-lead ECG 
will be recorded after the participant has rested for at least 5 minutes in a supine position.  
Data and evaluations from ECGs will be reported on the individual participants’ CRFs and transferred to 
Otsuka via the EDC database. Original ECG tracings will remain at the site (RRC) within the source 
documentation. 
6.5.8 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. After two minutes of 
standing, a second blood pressure reading (systolic and diastolic) and pulse rate will be obtained at the 
screening visit (V1). 
6.5.9 
Physical Examination 
A complete physical examination, including auscultation and palpation will be performed. A complete 
physical examination will include review of general appearance, hair and skin, head, eyes, ears, nose and 
throat, neck, chest, abdomen, dentition, cardiovascular, musculoskeletal and neurological systems. The 
physical examination is to be conducted by a designated fully trained representative. 
Appropriate medical recommendations will be provided to the participant if any medical findings 
requiring health care are identified. 
6.5.10 Expired Air CO Breath Test 
Carbon Monoxide (CO) in participant’s exhaled breath (expressed as ppm) will be measured using a 
Vitalograph BreathCO Monitor. Participants must have an expired air CO reading at V1 of at least 10 
ppm for inclusion into this study. This test will be repeated at each of the visits. 
6.5.11 Medical History and Concomitant Disease 
Relevant medical history and concomitant disease will be documented at the screening visit (V1). 
Medical history is defined as any condition that started and ended prior to screening. A concomitant 
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disease is defined as any condition that started prior to screening and is still ongoing at V2 (this may also 
include findings detected during the screening visit (V1)). 
6.5.12 Prior and Concomitant Medication 
All medication taken 30 days prior to the screening visit (V1) and during the study will be documented. 
Medications which are stopped before V2 will be considered as prior medications. Medications which 
are started prior to the screening visit (V1) and which are still being taken by the participant during the 
study, as well as medications that are initiated after the screening visit (V1) will be considered as 
concomitant medications. This applies to both prescription and over-the-counter products (e.g., 
vitamins). 
Records of prior and concomitant medications taken include the drug name (preferably both generic 
and trade name), route of administration, dose/unit, frequency of use, indication, the start and, if 
applicable, the stop date. Any therapy changes (including changes of regimen) during the study will be 
documented. 
6.5.13 Body Height and Body Weight 
Body weight will be measured at each visit. Height and weight will be measured at screening, and body 
mass index (BMI) will be calculated. 
6.5.14 Demographics 
Sex assigned at birth, sex currently identified with, date of birth, race and ethnicity will be recorded for 
each participant according to the Schedule of Events. 
6.5.15 AE/SAE Reporting 
AEs/SAEs will be assessed using questionnaires and interviews at the indicated time points and 
spontaneous reporting from the time of ICF signature until the EOS for the participant the Schedule of 
Events. 
6.5.16 Questionnaires 
The questionnaires will be administered to the participants using paper questionnaires and/or an 
electronic data collection system. The questionnaires will be asked according to the Schedule of Events. 
 C-SSRS – The Columbia-Suicide Severity Rating Scale  
The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior.24 The “Screening” 
Version will be used for the first administration (at the screening visit). This version will include an 
assessment of suicidal ideations over the past 12-months and an assessment of suicidal behaviors over 
the past 24 months. Subsequent visits will utilize the “Since Last Visit” Version.  
 Modified Cigarette Evaluation Questionnaire Extended (mCEQE)  
The Cigarette Evaluation Questionnaire was initially developed in the PI's laboratory and used in 
numerous studies to assess the effects of pharmacological treatments on the rewarding effects of 
cigarette smoking. The mCEQE will be utilized to assess the degree to which participants experience the 
reinforcing of smoking, providing five subscale scores: smoking satisfaction (satisfying, tastes good, 
enjoy smoking), psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger), aversion (dizziness, nauseated), enjoyment of respiratory tract sensations (single-item 
assessment), craving reduction (single-item assessment). Participants will be asked to assess the 12 
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items of the questionnaire on a 7-point scale, ranging from “not at all” to “extremely”. These 12 items 
will be asked for the “first cigarette smoked”, “cigarette immediately after a meal”, and “all other 
cigarettes.” 
 Modified Shiffman-Jarvik Withdrawal Scale 
The Modified Shiffman-Jarvik Withdrawal Scale is used to measure withdrawal symptoms and a 
participant’s desire to smoke. This scale consists of five subscales: craving, psychological symptoms, 
physical symptoms, sedation, and appetite.25  
 Reasons to Smoke 
The Reasons to Smoke questionnaire is used to determine the most important reasons to smoke for 
each participant. 
 The Fagerström Test for Nicotine Dependence (FTND) 
The Fagerström Test for Nicotine Dependence is a six-item questionnaire developed by Karl-Olov 
Fagerström and is used to determine someone’s level of nicotine dependence. The scores obtained on 
the test allow the classification of nicotine dependence in three different levels: mild (0-3 points), 
moderate (4-6 points), and severe (7 -10 points).  
 Smoking History Questionnaire 
The Smoking History is a questionnaire designed to help assess the participant’s current and past 
smoking habits. This questionnaire will be administered at screening (V1) and will include questions 
about the number of years participants have smoked combustible cigarettes (CC), the number of CCs per 
day smoked over the last 12 months, brand of CCs, use of other tobacco products and use of nicotine 
replacement therapy or other smoking cessation treatments. This questionnaire will also be used to 
check eligibility criteria. 
 Other Nicotine Use Questionnaire 
The Other Nicotine Use questionnaire will be used to capture information about the use of nicotine 
containing products (other than combustible cigarettes). This questionnaire will be given at V2 and all 
subsequent visits, including safety follow-up.  
 Minnesota Nicotine Withdrawal Scale (MNWS) 
The MNWS is used to assess nicotine withdrawal symptoms including craving and mood effects. 
Participants will be asked to assess eight symptoms on a 5-point scale ranging from 0 to 4, where 0 = 
none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe. 
 Study Drug Compliance 
Participants will be queried via electronic messages whether they have been compliant with taking the 
study drug. These messages will commence after the second visit (V2) and continue through the End of 
Study. 
 Smoking Status 
Electronic messages will be sent to participants starting after the second visit (V2), through the End of 
Study, to ascertain the participants smoking status. 
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6.6 VISIT PROCEDURES 
6.6.1 
Screening (V1) 
Eligibility of participants to participate in this study will be assessed at the screening visit (V1). The ICF 
will be signed, dated and timed prior to any other screening procedures. At the end of this visit, 
participants will be given instructions on the use of the messaging and questionnaire system that will be 
used daily to collect information about smoking status (starting the next day) and IMP compliance (after 
V2). 
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee) after signature of the ICF. Whenever possible, blood draws should be 
performed after all other assessments are complete. 
 
Questionnaires 
• Smoking History 
• Registration Form 
• Medical History (with Review of Systems) 
 
Assessments 
• Review of Prior and Concomitant Medication 
• Review of Concomitant Disease and Medical History 
• Expired air CO breath test  
• Alcohol breath test 
• Urine collection for urinalysis and drug screen 
• Blood collection for safety laboratory testing (including pregnancy test for all females) and 
for future biospecimen research (for those participants who consented to this optional 
collection) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. After 
two minutes of standing, a second blood pressure reading (systolic and diastolic) and pulse 
rate will be obtained. 
• Height and weight / BMI 
• Temperature 
• Electrocardiogram (ECG) -- A standard 12-lead ECG will be recorded after the participant 
has rested for at least 5 minutes in a supine position. 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Physical examination 
6.6.2 
Baseline (V2) – Day -1 
Visit 2 will occur within 28 days of the screening visit. Participants will come to the Center to complete 
questionnaires, assessments, and for dispensing of IMP. Participants will begin the study drug regimen 
the day after V2 (Day 1). Date and time of first dose will be collected via electronic message. 
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee).  
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Questionnaires 
• Reasons to Smoke 
• Other Nicotine Use Questionnaire 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
• Modified Shiffman-Jarvik Withdrawal Scale 
• Fagerström Test for Nicotine Dependence  
 
Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Expired air CO breath test  
• Urine collection for pregnancy (all participants with the potential to become pregnant) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. 
• Weight 
• Temperature 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Review of adverse events (as needed) 
• Physical examination (as needed) 
6.6.3 
Day before Quit Day (V3) – 1 week on IMP 
Six days (+ 3 days) after starting the study drug (one day prior to quit date), participants will return to 
the Center to complete questionnaires and assessments. Participants will also be asked to return unused 
IMP and will be dispensed enough IMP to last until the next scheduled visit.  
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee).  
 
Questionnaires 
• Other Nicotine Use Questionnaire 
• Modified Shiffman-Jarvik Withdrawal Scale 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
 
Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Expired air CO breath test  
• Urine collection for pregnancy (all participants with the potential to become pregnant) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. 
• Weight 
• Temperature 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
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• Review of adverse events (as needed) 
• Physical examination (as needed) 
6.6.4 
Visit 4 (V4) – 3 weeks on IMP 
Three weeks (± 3 days) after starting the study drug , participants will return to the Center for V4 to 
complete questionnaires and assessments. Participants will also be asked to return unused IMP and will 
be dispensed enough IMP to last until the next scheduled visit.   
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee).  
 
Questionnaires 
• Other Nicotine Use Questionnaire 
• Modified Shiffman-Jarvik Withdrawal Scale 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
 
Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Expired air CO breath test  
• Urine collection for drug screen and pregnancy (all participants with the potential to become 
pregnant) 
• Blood collection for safety laboratory testing, pharmacokinetics, and future biospecimen 
research (for those participants who consented to this optional collection) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. 
• Weight 
• Temperature 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Review of adverse events (as needed) 
• Physical examination (as needed) 
6.6.5 
Visit 5 (V5) – 5 weeks on IMP 
Five weeks (± 3 days) after starting the study drug, participants will return to the Center for V5 to 
complete questionnaires and assessments. Participants will also be asked to return unused IMP and will 
be dispensed enough IMP to last until the next scheduled visit. 
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee).  
 
Questionnaires 
• Other Nicotine Use Questionnaire 
• Modified Shiffman-Jarvik Withdrawal Scale 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
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Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Expired air CO breath test  
• Urine collection for drug screen and pregnancy (all participants with the potential to become 
pregnant) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. 
• Weight 
• Temperature 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Review of adverse events (as needed) 
• Physical examination (as needed) 
6.6.6 
Final Study Visit (V6) – 7 weeks on IMP 
Seven weeks (± 3 days) after starting the study drug, participants will return to the Center for V6 to 
complete questionnaires and assessments. Participants will also be asked to return all unused IMP. 
The sequence of the following questionnaires and assessments will be at the discretion of the 
Investigator (or designee).  
 
Questionnaires 
• Other Nicotine Use Questionnaire 
• Modified Shiffman-Jarvik Withdrawal Scale 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
• Fagerström Test for Nicotine Dependence  
 
Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Expired air CO breath test  
• Alcohol breath test 
• Urine collection for urinalysis and pregnancy (all participants with the potential to become 
pregnant) 
• Blood collection for safety laboratory testing, pharmacokinetics, and future biospecimen 
research (for those participants who consented to this optional collection) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate), will be 
measured in sitting position after the participant has rested for at least 5 minutes. 
• Weight 
• Temperature 
• Electrocardiogram (ECG) -- A standard 12-lead ECG will be recorded after the participant has 
rested for at least 5 minutes in a supine position. 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Review of adverse events (as needed) 
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• Physical examination (as needed) 
6.6.7 
Telephone Contact 
Participants will be contacted via phone on Day 1 (first day of IMP) and on weeks that they are not 
scheduled to visit the Center (Wk 2, Wk 4, and Wk 6) to ask how they are doing and answer any 
questions the participant may have.  
6.6.8 
Safety Follow-Up 
Seven to 10 days after V6, participants will be contacted via phone for a safety follow-up.  
 
Questionnaires 
• Other Nicotine Use Questionnaire 
• Modified Cigarette Evaluation Questionnaire Extended (mCEQE) 
• Minnesota Withdrawal Questionnaire 
 
Assessments 
• Review of Concomitant Medication 
• Review of Concomitant Disease 
• Review of adverse events  
6.7 DAILY MESSAGING 
Rose Research Center will utilize eResearch, an IRB approved proprietary mobile electronic application 
for clinical research studies available in both the iOS and Android app stores. For the purposes of this 
protocol, the Survey’s feature will be utilized to push the daily messages to enrolled participants. 
Daily text reminders and/or push notifications may be paired with these daily messages in order to 
remind participants about the request to complete these assessments.  
6.7.1 
Daily Message (after screening, prior to V2) 
Participants will receive a push notification with a prompt to a daily survey to access the following: 
• Have you smoked any combustible cigarettes today? 
o If yes, how many cigarettes did you smoke? 
6.7.2 
Daily Message (Visit 2 through V6) 
Participants will receive a push notification with a prompt to a daily survey to assess the following: 
• Have you smoked any combustible cigarettes today? 
o If yes, how many cigarettes did you smoke? 
• Did you take your 1st dose of study drug today? 
• Did you take your 2nd dose of study drug today? 
o If yes, did you take the 2nd dose 4 to 6 hours after the 1st dose? 
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6.8 SCHEDULE OF EVENTS 
  
Table 6 - Schedule of Event 
Study Week
SCR
Wk 0
Baseline
Wk 1
(+ 3 days)
Wk 2 - Wk 3
(± 3 days)
Wk 4 - Wk 5 
(± 3 days)
Wk 6 - Wk 7 
(± 3 days)
Wk 8
(+ 2 days)
Visit
V2
V3
V4
V5
V6
IMP Timeline
Day -1
Day 1 IMP
Wk 1 IMP
Wk 3 IMP
Wk 5 IMP
Wk 7 IMP
Informed Consent
x
Inclusion/Exclusion Criteria
x
 x 
Enrollment
 x 
Visit Preparation
x
 x 
 x 
 x 
 x 
 x 
Visit Reminder Calls
x
 x 
 x 
 x 
 x 
 x 
Telephone Contact -(Day 1, Wk 2, Wk 4, Wk 6, and 7 day F/U)
 x 
 x 
 x 
 x 
 x 
Reasons to Smoke
 x 
Smoking History
x
Other Nicotine Use
 x 
 x 
 x 
 x 
 x 
 x 
Registration Form
x
Medical History with Review of Systems
x
Modified Cigarette Evaluation Questionnaire Extended (mCEQE)
 x 
 x 
 x 
 x 
 x 
 x 
The Fagerström Test for Nicotine Dependence (FTND)
 x 
 x 
Modified Shiffman-Jarvik Withdrawal Scale
 x 
 x 
 x 
 x 
 x 
Minnesota Withdrawal Questionnaire
 x 
 x 
 x 
 x 
 x 
 x 
The Columbia-Suicide Severity Rating Scale (C-SSRS)
x
x
x
x
x
x
 Smoking Status  (via daily messages )
x
 x 
 x 
 x 
 x 
 x 
 x 
Medication Adherence (via daily messages)
 x 
 x 
 x 
 x 
 x 
 x 
Clinical Chemistry
x
 x 
 x 
CBC w/Diff & Platelet Count
x
 x 
 x 
Serum Pregnancy Test*
x
HbA1c
x
PK Blood Draws
 x 
 x 
Urinalysis Safety Panel
x
 x 
Drug Screen
x
 x 
 x 
Pregnancy 
 x 
 x 
 x 
 x 
 x 
Prior and Concomitant Medication Assessment and Medical Review
x
 x 
 x 
 x 
 x 
 x 
 x 
Concomitant Disease Assessment and Medical Review
x
 x 
 x 
 x 
 x 
 x 
CO Breath Test
x
 x 
 x 
 x 
 x 
 x 
ECG
x
 x 
Blood Pressure - Sitting and Standing Positions
x
 x 
 x 
 x 
 x 
 x 
Heart rate
x
 x 
 x 
 x 
 x 
 x 
Temperature
x
 x 
 x 
 x 
 x 
 x 
Respiratory rate
x
 x 
 x 
 x 
 x 
 x 
Weight
x
 x 
 x 
 x 
 x 
 x 
Physical Examination (as needed)
x
 x 
 x 
 x 
 x 
 x 
Alcohol Breath Test
x
AE Interview and Assessment
 x 
 x 
 x 
 x 
 x 
 x 
Collect Used/Unused IP
 x 
 x 
 x 
 x 
Dispense IP
 x 
 x 
 x 
 x 
IMP Dosing
 x 
 x 
 x 
 x 
 x 
* Serum pregnancy test will be done if urine pregnancy test is positive
Other Assessments
Procedures
Safety 
Follow-up
Questionnaires
Blood Samples
Urine Samples
V1
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 RISK / BENEFIT INFORMATION 
7.1 POTENTIAL BENEFITS 
The participants will be encouraged to quit smoking, which would significantly reduce their risk of 
smoking-related diseases. 
7.2 IMPORTANCE OF KNOWLEDGE TO BE GAINED 
The proposed study could lead to the development of a new approach to smoking cessation that would 
have a major positive impact on public health worldwide along with associated comorbid conditions. 
7.3 POTENTIAL RISKS 
7.3.1 
Centanafadine SR 
The most common adverse effects reported in other studies of centanafidine SR include: decreased 
appetite, headache, nausea, dry mouth diarrhea, fatigue, insomnia, rash (refer to Section 9.5 for 
additional information), dizziness, heart rate increase when standing from a sitting position, irritability, 
abdominal pain, change in sense of taste.1 
7.3.2 
Tobacco Withdrawal 
To the extent that nicotine or other tobacco smoke constituent intake is reduced or eliminated, 
participants may experience tobacco withdrawal symptoms, including craving, difficulty concentrating, 
mood disturbance and increased appetite/weight gain.  
7.3.3 
Blood Draw 
The risks associated with venipuncture are minimal and include momentary discomfort and/or bruising. 
Infection, excess bleeding, clotting, and fainting are also possible, although unlikely. 
7.4 CONCOMITANT MEDICATIONS 
All medication taken 30 days prior to the screening visit (V1) and during the study will be documented 
using a source document. Medications which are stopped before V2 will be considered as prior 
medication. Medication which was started prior to V1 and which is still being taken by the subject during 
the study as well as medication that is initiated after V2 will be considered as a concomitant medication. 
This applies to both prescription and over-the-counter products (e.g., vitamins). 
Records of prior and concomitant medications taken include the drug name (preferably both generic 
and trade name), route of administration, dose/unit, frequency of use, indication, the start and if 
applicable, the stop date. Any therapy changes (including changes of regimen) during the study have to 
be documented. 
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7.5 PROTECTION AGAINST RISKS 
Participants will be screened medically and monitored throughout the study. Study participants will 
receive detailed instructions on the use of the IMP distributed to them, in order to minimize the 
possibility of misuse. Participants will be instructed to keep the study drug away from children and pets. 
Participants will be instructed to report any side effects to study staff, who will communicate these 
reports to the medical staff. The most appropriate course of action will be determined, which may 
include options for termination of exposure to the study drug. Participants will, however, be reminded 
that they have the option to withdraw from the study at any time. Participants will also be given a 24-
hour emergency contact number in the event that side effects or adverse events occur between 
sessions. 
7.5.1 
Blood Pressure Monitoring 
Cigarette smoking affects blood pressure in many ways, including stimulation of the sympathetic 
nervous system, but also through acute inflammation, impairment of endothelial function, and 
increased arterial stiffness.26 In 2017, the American College of Cardiology set forth stricter 
recommendations for treatment of elevated blood pressure, with the goal of commencing treatment 
(lifestyle changes and/or medication) starting at 130/80, vice 140/90.27 The definition of systemic 
arterial hypertension (commonly known as hypertension) did not change with these new 
recommendations from the American College of Cardiology. Hypertension is characterized by 
persistently high blood pressure in the systemic arteries, with an “Office BP” of > 140 mmHg systolic and 
> 90 mmHg diastolic.28 
This study will use a blood pressure of 150/95 as a cutoff for eligibility, recognizing that most 
participants have recently smoked just prior to arriving for the screening process, and that many of 
them will have additional sympathetic activation through the ingestion of caffeinated beverages.   
Any participant who presents with blood pressure > 140 mmHg systolic and/or > 90 mmHg diastolic will 
be counselled, with recommendations to monitor blood pressure at home and follow up with their 
primary care provider. Participants who enroll in the study will have blood pressure checks at every 
office visit. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 MONITORING ACTIVITIES 
An independent Monitor will be contracted by RRC and will be responsible for the monitoring activities. 
Monitoring will be performed as per the agreed monitoring plan. A minimum of the following types of 
monitoring visits will occur for this study. 
8.1.1 
Site Initiation Visit (SIV) 
A Site Initiation Visit will be conducted by the Monitor prior to site activation to confirm preparedness 
for protocol execution, satisfactory site facilities, clarify the applicable regulations and requirements of 
the protocol, carefully review the process of implementing the protocol at the site and conduct any 
necessary training prior to activating the site for enrollment. 
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8.1.2 
Interim Monitoring Visits (IMVs)  
Interim Monitoring Visits will be conducted to confirm participants’ rights are being protected; the study 
is being conducted according to the protocol and applicable regulations; and to confirm accurate 
reporting of participant safety data and study endpoints. 
8.1.3 
Close-Out Visit (COV)  
A Close-Out Visit will be conducted to ensure that all study data and other study documentation is 
complete and accurate and that all study records have been reconciled. 
8.2 TRAINING OF STAFF 
The Investigator or designee will ensure that appropriate training relevant to the study is provided to all 
staff involved in the study, and that any new information relevant to the performance of this study is 
forwarded in a timely manner to the staff.  
8.3 AUDITS AND INSPECTIONS 
Good Clinical Practice regulations require independent inspections of clinical program activities. Such 
inspections may be performed at any time before, during, and after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed and accurately reported, according to the 
protocol, ICH/GCP guidelines and any applicable regulatory requirements. The Investigator or designee 
will contact the Sponsor immediately if contacted by a regulatory agency about an inspection at their 
site. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate filing 
system of all study-related documentation that will be suitable for inspection at any time by the 
Sponsor, its authorized representative, and other regulatory agencies.  
 ADVERSE EVENTS 
9.1 DEFINITIONS 
9.1.1 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a patient or clinical trial participant 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. The AEs would not include information recorded as medical history at screening for 
preplanned procedures for which the underlying condition was known and no worsening occurred. An 
adverse reaction is any untoward and unintended response to an IMP-related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the IMP caused 
the AE. For the purpose of Investigational New Drug (IND) safety reporting, “reasonable possibility” 
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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. 
Any increase in the severity and/or the frequency of a concomitant disease is considered an AE. 
9.1.2 
Serious Adverse Event (SAE) 
A Serious Adverse Event is any adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening; ie, the participant was, in the opinion of the investigator, at immediate risk 
of death from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death. 
• Persistent or significant incapacity/disability or substantial disruption of the ability to conduct 
normal life functions. 
• Requires in-patient hospitalization or prolongs hospitalization. 
o Hospitalization itself should not be reported as an SAE; whenever possible the reason 
for the hospitalization should be reported. 
o Hospitalizations or prolonged hospitalizations for social admissions (ie, those required 
for reasons of convenience or other non-medical need) are not considered SAEs. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical judgment, may 
jeopardize the participant 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. 
9.1.3 
Nonserious Adverse Event 
Adverse events are all AEs that do not meet the criteria for a "serious" AE. 
9.1.4 
Immediately Reportable Event (IRE) 
The following events will be reported immediately to the Sponsor. 
• Any SAE. 
• Any AE of special interest (AESI). 
• Any AE related to occupational exposure. 
• Potential serious hepatotoxicity. 
• Confirmed pregnancy. 
9.1.5 
Psychiatric Adverse Events 
The investigator (or designee) will review participant responses to the C-SSRS. The C-SSRS will be used to 
screen for suicidal ideation within the last 12 months and suicidal behavior within the last 24 months 
from screening. Potential participants who score >0 on the screening C-SSRS for suicidal ideations 
(answer “Yes” to questions 1-5 in the SUICIDAL IDEATION section) or a score >0 for Suicidal Behavior 
(answer “Yes” to any questions in the SUICIDAL BEHAVIOR section) at screening (Visit 1) or at Baseline 
(Visit 2) will be excluded from study participation, and, at the discretion of the study physician/physician 
assistant, referred to appropriate psychiatric treatment. The C-SSRS will be administered by trained 
clinical research staff at every visit, including the screening visit (V1 through V6). The “Screening” 
version will be administered at V1, and the “Since Last Visit” version will be administered at V2 through 
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V6, inclusive. Any changes in the scoring will be evaluated by licensed medical professionals, with 
recommendations for referral to appropriate medical care provided to the participant when required, at 
the discretion of the study physician/physician assistant. 
9.1.6 
Changes in Clinical Laboratory Test Values 
It is the investigator’s (or designee’s) responsibility to review the results of all laboratory tests as they 
become available. This review will be documented by the investigator’s dated signature on the 
laboratory report. For each abnormal laboratory test result, the investigator needs to ascertain if this is 
an abnormal (ie, clinically significant) change from baseline for that individual participant. This 
determination, however, does not necessarily need to be made the first time an abnormal value is 
observed. The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically relevant by the 
investigator (participant 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. 
9.2 COLLECTION OF SAFETY EVENTS FROM PARTICIPANTS 
The investigator will periodically assess participants for the occurrence of AEs. To avoid bias in eliciting 
AEs, participants should be asked the non-leading question: “How have you felt since your last visit?”  All 
AEs (serious and nonserious) reported by the participant must be recorded on the source documents 
and eCRF. Serious AE collection is to begin after a participant has signed the eICF.  
Use medical terminology in AE reporting. Adverse events should be reported as a single unifying 
diagnosis whenever possible or, in the absence of a unifying diagnosis, as individual signs or symptoms. 
Exacerbation or disease progression should be reported as an AE only if there are unusual or severe 
clinical features that were not present, or experienced earlier, or not expected based on the course of 
the condition. 
Information recorded when collecting AEs will include: thorough description of the AE, seriousness 
assessment, start and stop dates (if known), circumstances leading up to the event, clinical elements 
such as clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence, the action taken with the investigation 
product/procedures due to the AE, the participant`s disposition in the study after the occurrence of the 
AE and the final outcome of the AE (if known). 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall be 
evaluated and recorded. 
9.2.1 
Period of Collection 
All existing health conditions identified during the Screening Period will be recorded as concomitant 
disease and the participant’s eligibility will be reviewed. Any AEs which occur during the screening 
session will be captured by the study site staff and assessed by the Investigator or designee in order to 
establish relationship or relatedness in respect to study procedures. 
Any new, clinically relevant, abnormal finding detected during the study or worsening of a pre-existing 
condition/concomitant disease will be documented as an AE or an SAE. 
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All ongoing AEs at the End of Study participation will be followed-up by the Investigator or designee until 
they have improved, resolved, stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found. The Investigator or designee will refer the participant to their Primary Care 
Provider for follow up of those AE when appropriate. 
9.3 ASSESSMENT OF ADVERSE EVENTS 
9.3.1 
Severity of Adverse Events 
For each AE/SAE, the intensity will be graded on a 3-point intensity scale: 
• Mild:  The AE is easily tolerated and does not interfere with daily activity. 
• Moderate: The AE interferes with daily activity, but the participant is still able to function. 
• Severe: The AE is incapacitating and requires medical intervention. 
9.3.2 
IMP Causality 
In general, all AEs and SAEs will be assessed by the Investigator or designee as either ‘related’ or ‘not 
related’.  
• Not related: The temporal relationship of the clinical event to study procedures and/or the 
study medication makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient explanation for the 
observed event. 
• Related: The temporal relationship of the clinical event to study procedures and/or the study 
medication makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for the 
observed event. 
9.4 IMMEDIATELY REPORTABLE EVENTS 
The investigator must immediately report after either the investigator or site personnel become aware 
of any SAE, AE related to occupational exposure, AESI, potential serious hepatotoxicity, or confirmed 
pregnancy, by telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
of this protocol. An IRE form must be completed and sent by e-mail, fax, or overnight courier to the 
sponsor (Please note that the IRE form is NOT the AE eCRF). 
Subjects experiencing SAEs should be followed clinically until their health has returned to baseline 
status, or until all parameters have returned to normal or have otherwise been explained. It is expected 
that the investigator will provide or arrange appropriate supportive care for the subject and will provide 
prompt updates on the subject’s status to the sponsor. 
9.5 ADVERSE EVENTS OF SPECIAL INTEREST 
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9.6 ABUSE POTENTIAL MONITORING PLAN 
A key objective of the Abuse Potential Monitoring Process (APMP) is to monitor for instances of abuse 
or diversion of the trial medication and other psychoactive substances. In addition to monitoring for 
irregularities in medication handling, AEs that may be suggestive of a developing abuse issue will also 
receive special attention. As part of the APMP, medication handling irregularities (MHIs) must be 
reported, and AEs related to abuse potential and AEs involving MHIs must be reported as Events Subject 
to Additional Monitoring (ESAMs) with detailed narratives.  
Investigators and site staff at each trial site will be trained on reporting potentially abuse related AEs 
(eg, recording a description of the event in the participant’s own words in the source documents as well 
as the eCRF, in addition to the clinical term, and to be aware that a participant’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).29 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. 
9.7 POTENTIAL SERIOUS HEPATOTOXICITY 
For a participant who experiences an elevation in aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) that is 3 times the upper limit of normal (ULN), a total bilirubin level should also 
be evaluated. If the total bilirubin is 2 times the ULN, complete an IRE form with all values listed and also 
report as an AE on the eCRF. 
9.8 PREGNANCY AFTER ENROLLMENT 
During the trial, all FOCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (eg, missed or late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration must be 
withheld until the results of serum pregnancy tests are available. If the pregnancy is confirmed, the 
subject must not receive the IMP and must not be enrolled in the trial. If pregnancy is suspected while 
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the subject is taking IMP, the IMP must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the pregnancy test is known. If 
pregnancy is confirmed, the IMP will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety) and the subject will be withdrawn from the trial. 
The investigator must immediately notify the sponsor of any pregnancy associated with IMP exposure 
during the trial and for 30 days after the last dose of IMP for female subjects, and for 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 Pregnancy Surveillance Form(s) for monitoring the outcome of 
the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed on the subject 
unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered, if indicated. In addition, the investigator must report to the sponsor, 
on appropriate Pregnancy Surveillance Form(s), follow-up information regarding the course of the 
pregnancy, including perinatal and neonatal outcome. Infants should be followed for a minimum of 6 
months from the date of birth, if consent is given to do so.  
9.9 FOLLOW-UP OF NON-SERIOUS ADVERSE EVENTS 
Nonserious AEs that are identified at any time during the trial must be recorded on the AE eCRF with the 
current status (ongoing or resolved/recovered) noted. All nonserious events (that are not IREs) that are 
ongoing at the last scheduled contact will be recorded as ongoing on the eCRF. For any AE having been 
identified throughout the trial, during analysis, additional relevant medical history information may be 
requested by the sponsor to further ascertain causality (including, but not limited to, information such 
as risk related behavior, family history and occupation). 
9.10 FOLLOW-UP OF SERIOUS ADVERSE EVENTS AND IMMEDIATELY REPORTABLE EVENTS 
This trial requires that participants be actively monitored for SAEs and IREs for 7-10 days after the last 
dose of IMP is administered. 
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled contact must be 
recorded as such on the AE eCRF page. If updated information (eg, resolved status) on SAE or IRE status 
becomes available after a participant’s last scheduled contact (up to last in-clinic visit for the entire 
trial), this must be reported to the sponsor according to the appropriate reporting procedures. The 
investigator will follow SAEs until the events are resolved, stabilized, or the participant is lost to follow 
up or has died. Resolution means that the participant has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or worsening of the 
participant’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 participant is lost to follow-up, or 
has died. 
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9.11 FOLLOW-UP AND REPORTING OF SERIOUS ADVERSE EVENTS AND IMMEDIATELY REPORTABLE 
EVENTS OCCURRING AFTER LAST SCHEDULED CONTACT 
Any new SAEs or IREs reported to the investigator which occur after the last scheduled contact and are 
determined by the investigator to be reasonably associated with the use of the IMP, should be reported 
to the sponsor. This may include SAEs or IREs that are captured on follow-up telephone contact or at any 
other time point after the defined trial period. The investigator should follow SAEs or IREs identified 
after the defined trial period and continue to report any significant follow-up information to the sponsor 
until the events are  resolved, stabilized, or the participant is lost to follow-up or has died. 
 DATA MANAGEMENT 
10.1 DATA COLLECTION PROCEDURES 
The results from the clinical assessments will be recorded in the source data file by the Investigator or 
their authorized designee and then captured in the case report forms (CRFs), unless otherwise specified 
in the final protocol. Trained study personnel will be responsible for capturing the data from the 
observations, tests, and assessments specified in the protocol and in the source documents. Study 
personnel will transfer the data to the CRFs. 
The Investigator has ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. Any corrections made to source documents 
must be clearly recorded, without obscuring the original values and be accompanied by the date of 
change, reason for change, and identification of the person making the change. CRF data will be verified 
against the source documents at the study site by appropriate staff. Instances of missing or unclear data 
will be discussed with the Investigator for resolution. 
10.2 PROTOCOL DEVIATIONS / NONCOMPLIANCE 
Protocol deviations are defined as deviations from the study procedures as defined in this document, 
whether intentional or unintentional. Protocol deviations that may affect the participant’s rights, safety, 
or well-being and/or the completeness, accuracy, and reliability of the data must be reported to the IRB 
within 10 business days of becoming aware of the deviation. 
Noncompliance is defined as any action or activity involving human subjects that fails to comply with 
applicable regulations. Noncompliance that meets this definition must be reported to the IRB within 10 
business days of becoming aware of the noncompliance. 
10.3 DATA CAPTURE 
All data are collected from participants using paper documents or an electronic data capture system. All 
applicable data, as specified in the protocol, will be transferred to the database or applicable Case 
Report Forms. 
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10.3.1 Pre-screening Data 
Data will be collected for recruitment and screening purposes as stated within an Advarra IRB generic 
recruitment protocol. Unrelated to that recruitment protocol, pre-screening questionnaires will be 
attached to potential participant’s records on whether they qualify or are disqualified for this study. Pre-
Screening questionnaires utilized for this study will be permanently attached to that potential 
volunteer’s record unless that information is requested to be removed by the participant. 
10.3.2 At-home Data Collection 
Electronic messaging will be utilized for the delivery of a link to a mobile device to collect study data. 
This data will be collected utilizing an electronic survey. The platform utilized for these messages will be 
eResearch, an IRB approved proprietary mobile research tool. Participants will be required to consent to 
use eResearch for daily at-home collection and be permitted to access the Survey functions for this 
protocol. The only other additional features available will be the standard publicly available ability to 
update and maintain their volunteer profile.  
10.3.3 Electronic Data Capture System 
All smoking behavioral and self-report measures will be captured using Medrio. All information collected 
within Medrio is compliant with 21 CFR 11 requirements. 
10.4 MISSING DATA 
Missing data will remain as missing, i.e., no attempt will be made to impute missing values.  
10.5 DATA HANDLING 
Data of all participants enrolled including screening failures and AE/SAEs during the study (from the time 
of informed consent to the end of the study of the participant) will be captured in the source 
documents. For screening failures, only consent date and reason for screen failure will be added to the 
CRFs. 
10.6 DATA VALIDATION 
Data of all participants enrolled including screening failures and AE/SAEs during the study (from the time 
of informed consent to the end of the study of the participant) will be captured in the source 
documents. 
10.7 DATABASE LOCK 
Upon completion of the trial, after data entry is complete, the data has been cleaned, and the principal 
investigator has reviewed and provided approval, the database will be locked, and final write access will 
be removed. 
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 PLANNED STATISTICAL METHODS 
All data measures (e.g., withdrawal symptoms questionnaires, smoking history, self-report daily smoking 
messages, etc.) are captured initially using paper or an electronic data capture system. Verified data files 
will be analyzed using SAS (SAS Institute, Cary NC).  
11.1 SAMPLE SIZE ESTIMATION 
 
 
 
 
 
 
 
 
 
 
 
 
11.2 STATISTICAL METHODS 
The estimation of the four-week continuous smoking abstinence rate at 6 weeks post target quit date is 
around 50% and 30% of treated individuals experiencing nausea from varenicline treatment based on 
the historical studies.2  The smoking abstinence rate during weeks 4-7 will be calculated with 90% 
binomial confidence intervals, and the incidence rate of nausea will be tabulated, which will be 
compared with the thresholds established for efficacy and tolerability. 
11.3 OUTCOMES 
In general, descriptive statistics  will be provided for all efficacy and safety outcomes when applicable. 
Details will be provided in statistical analysis plan (SAP). 
11.3.1 Smoking Abstinence 
Complete abstinence from combustible cigarette use at each time point will be defined by a self-report 
of no cigarette smoking (not even a puff) since the prior session, confirmed by an expired air CO reading 
of less than 5 ppm. The primary outcome will be four-week continuous smoking abstinence during 
weeks 4-7. An intent-to-treat approach will be taken in which any participants lost to follow-up after 
receiving the investigational product, or who have smoked during weeks 4-7 will be counted as non-
abstinent. 
11.3.2 Incidence of Nausea 
A secondary outcome measure will be the incidence of nausea at any timepoint after drug 
administration begins. 
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 ETHICS AND REGULATIONS 
12.1 IRB APPROVAL 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF], questionnaires, subject recruitment materials [e.g., advertisements, 
phone screening script], written information to be provided to the subjects, Investigators’ Brochure, the 
Investigator’s and designee’s curriculum vitae and/or other evidence of qualifications and any other 
documents requested by an Institutional Review Board [IRB], will be submitted for review and approval.  
Any change to the protocol must be submitted to the IRB for review and approval before 
implementation. A protocol change intended to eliminate an apparent immediate hazard to participants 
may be implemented immediately provided the reviewing IRB are notified within 10 working days. 
12.2 INVESTIGATIONAL NEW DRUG APPLICATION 
An Investigational New Drug (IND) application has been submitted to the FDA (IND 155242) for the use 
of centanafadine. 
12.3 GCP AND REGULATORY REQUIREMENTS 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
requirements. The study must be conducted in accordance with the regulations of the United States 
Food and Drug Administration (FDA) as described in 21 CFR 50 and 56, applicable laws and the IRB 
requirements.  
12.4 PARTICIPANT INFORMATION AND CONSENT 
It is the responsibility of the investigator to provide each participant with full and adequate verbal and 
written information using the IRB-approved informed consent form (ICF), including the objective and 
procedures of the study and the possible risks involved before inclusion in the study. Informed consent 
must be obtained prior to performing any study-related procedures.  
The signed and personally dated original and completed ICF(s) must be kept by the Investigator and filed 
in the Investigator study file at the site or with the participant’s files and a copy must be given to the 
participant. The participant will be informed that if they discontinue from the study, the data collected 
until the point of discontinuation will be maintained as part of the study data and the samples 
collected prior to discontinuation will be analyzed, unless they refuse in writing. 
12.5 AMENDMENT TO INFORMED CONSENT FORM 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of the ICF is 
necessary, the Investigator or designee will ensure that the documents have been reviewed and 
approved by the IRB before participants are informed and sign the amended ICF (including date and 
time). 
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 ADMINISTRATIVE CONSIDERATIONS 
13.1 PARTICIPANT CONFIDENTIALITY 
All information obtained during the conduct of the study with respect to the participants' state of health 
will be regarded as confidential. A statement to this effect will be written in the information provided to 
the participant. An agreement to disclose any such information will be obtained from the participant in 
writing and signed by the participant, in compliance with all local and national data protection and 
privacy legislation. 
Study records that identify participants will be kept confidential as required by law. Except when 
required by law, participants will not be identified by name, social security number, address, telephone 
number, or any other direct personal identifier in study records disclosed outside of Rose Research 
Center. For records disclosed outside of Rose Research Center, participants will be assigned a unique 
code number. The key to the code will be kept separate from the locked file where the study records are 
stored. 
13.2 RECORDS RETENTION 
13.2.1 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.  
13.2.2 Records Retention at the Trial Site 
Food and Drug Administration regulations require all investigators participating in clinical drug trials to 
maintain detailed clinical data for one of the following periods: 
• A period of at least 2 years after the date on which a New Drug Application is approved by the 
FDA; 
• A period of 2 years after the sponsor has notified the FDA that investigation with this drug is 
discontinued. 
The investigator must not dispose of any records relevant to this trial without either (1) written 
permission from the sponsor or (2) provision of an opportunity for 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. 
13.3 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 
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(http://www.icmje.org/recommendations). According to ICMJE guidelines, one may be considered an 
author only if the following criteria are met: 
• Substantial contributions to the conception or design of the work; or the acquisition, analysis, 
or interpretation of data for the work; AND 
• Drafting the work or revising it critically for important intellectual content; AND 
• Final approval of the version to be published; AND 
• 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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28.  Oparil S, Acelajado MC, Bakris GL, et al. Hypertension. Nat Rev Dis Primer. 2018;4:18014. 
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Appendix 2 – Fagerström Test for Nicotine Dependence (FTND) 
 
 
 
 
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Appendix 3 – Smoking History 
 
 
 
 
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Appendix 4 – Other Nicotine Use Questionnaire 
 
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Appendix 5 – Modified Cigarette Evaluation Questionnaire – Extended (mCEQE) 
 
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Appendix 6 – Reasons to Smoke 
  
 
 
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Appendix 7 – Shiffman Jarvik Withdrawal Scale 
 
 
 
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Appendix 8 – Minnesota Nicotine Withdrawal Scale 
 
 
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Document Name: 405-201-00055 Protocol Amendment 1
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Biostatistics Approval
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