Clinical trial NCT03471767
Conditions: Smoking Cessation Smoking, Cigarette Nicotine Dependence
Keywords: Smoking cessation Nicotine dependence Bupropion DXM Nicotine addiction Cigarette smoking Dextromethorphan
Sponsor: James Davis
Start date: 2018-03-25; Completion date: 2019-03-31
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is designed with the purpose of evaluating a new drug, combination Dextromethorphan-Bupropion (AXS-05), for its effects on smoking behavior.

Detailed description:
This study aims to investigate the potential efficacy of a combination of two FDA-approved agents, sustained release (SR) Bupropion (BUP) and immediate release (IR) Dextromethorphan (DXM), for the purpose of smoking cessation treatment. DXM, a widely used over-the-counter cough suppressant, is a nicotine receptor antagonist. In fact, studies by Duke's Center for Smoking Cessation (CSC) have shown that administration of DXM leads to a decrease in self-administration of nicotine in nicotine-dependent rats. DXM, however, has not been studied in humans. DXM, when taken alone, is not expected to be useful for treating nicotine dependence in humans given DXM rapidly metabolizes in humans via CYP2D6. As a result, therapeutic concentrations needed to bind to nicotine receptors are not obtained. Therapeutic concentrations of DXM are required, therefore, to allow DXM to bind to nicotine receptors and act as a nicotine antagonist. In order to attain therapeutic concentrations of DXM a metabolism inhibitor must be introduced. BUP is a well-known FDA approved smoking cessation medication that has been shown to inhibit the metabolism of DXM. When BUP is co-administered with DXM to healthy volunteers, a significant increase in DXM plasma levels is observed.

Currently, Axsome Therapeutics Inc. (Axsome) is developing and testing an oral fixed-dose combination of IR DXM with SR BUP to achieve therapeutic concentrations of DXM. This investigational drug has been named AXS-05. Axsome has found AXS-05 to be generally safe and well-tolerated in three Phase 1 studies. The adverse event profile of AXS-05 was similar to that of BUP alone.

Given the distinct mechanisms by which BUP and DXM interact, it is hoped that combining DXM and BUP will prove more efficacious than either drug administered alone for the purpose of tobacco use treatment in humans.

Arms: arm 1: Participants will receive AXS-05 (Dextromethorphan Immediate Release + Bupropion Sustained Release) for 4 weeks and will be instructed to take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal. arm 2: Participants will receive Bupropion SR (Bupropion Sustained Release) for 4 weeks and will be instructed to take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal.
Interventions: intervention 1: AXS-05 intervention 2: Bupropion SR
Intervention descriptions: intervention 1: Dextromethorphan Immediate Release + Bupropion Sustained Release: Take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal. intervention 2: Bupropion Sustained Release: Take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal.

Protocol documents:
Prot_SAP_000.pdf: 
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AXS-05 on Smoking Behavior 
1
A Supportive Care-Drug Intervention Study 
A Randomized, Double-Blind 4-Week Study  
to Evaluate the Impact of AXS-05 on Smoking Behavior  
NCT03471767 
 
 
 
 
 
Sponsor-Investigator: 
 
Dr James Davis – Duke Cancer 
Institute  
 
 
Funding Source: 
Axsome Therapeutics Inc.   
 
 
Protocol Source: 
Dr. James Davis - Duke Cancer 
Institute 
 
 
 
Duke IRB#: 
 
 
Pro00089413 
 
 
 
Principal Investigator 
James Davis, MD 
2424 Erwin Road, Suite 201, Durham, NC 
Phone: 919-668-5055 
Fax: 919-668-5088 
james.m.davis@duke.edu  
 
Statistician 
Paul Dennis, Ph.D. 
Paul.dennis@duke.edu  
 
Medical Supervisor  
Eric Langhans, PA 
Eric.langhans@duke.edu 
 
Study Coordinator 
Leah Thomas 
leah.thomas@duke.edu 
 
INFORMATION ON AXS-05 IN THIS PROTOCOL WAS OBTAINED FROM AXSOME THERAPEUTICS INC. AND IT IS 
PROPRIETARY. INFORMATION IN THIS PROTOCOL MAY BE USED ONLY FOR PURPOSES OF THIS STUDY  
 
 
Original version: 
01/09/2018 
 
 
 
 


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1. TABLE OF CONTENTS 
 
1. 
TABLE OF CONTENTS ........................................................................................... 2 
2. 
LIST OF ABBREVIATIONS .................................................................................... 4 
3. 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ................................... 5 
3.1. 
Purpose ................................................................................................................... 5 
3.2. 
Background and Significance ............................................................................... 7 
3.3. 
Design and Procedure ........................................................................................... 9 
3.4. 
Selection of Subjects .............................................................................................. 9 
3.5. 
Duration of study ................................................................................................. 12 
3.6. 
Data Analysis and Statistical Considerations ................................................... 12 
4. 
STUDY SCHEMA .................................................................................................... 14 
5. 
BACKGROUND AND SIGNIFICANCE .............................................................. 15 
5.1. 
Study Condition ................................................................................................... 15 
5.2. 
Study Drug ........................................................................................................... 16 
5.3. 
Study Purpose/Rationale ..................................................................................... 18 
6. 
OBJECTIVES AND ENDPOINTS ......................................................................... 20 
7. 
INVESTIGATIONAL PLAN .................................................................................. 21 
7.1. 
Study Design ......................................................................................................... 21 
7.2. 
Rationale for Selection of Dose, Regimen, and Treatment Duration ............. 27 
7.3. 
Rationale for Correlative Studies ....................................................................... 27 
7.4. 
Definition of Evaluable Subjects, On Study, and End of Study ...................... 27 
7.5. 
Early Study Termination .................................................................................... 27 
8. 
STUDY DRUG .......................................................................................................... 28 
8.1. 
Names, Classification, and Mechanism of Action............................................. 28 
8.2. 
Packaging and Labeling ...................................................................................... 28 
8.3. 
Supply, Receipt, and Storage .............................................................................. 28 
8.4. 
Dispensing and Preparation ............................................................................... 28 
8.5. 
Compliance and Accountability ......................................................................... 28 
8.6. 
Disposal and Destruction .................................................................................... 28 
9. 
ELIGIBILITY .......................................................................................................... 29 
10. TRIAL PROCEDURES AND ASSESSMENTS ................................................... 30 
10.1. Screening Examination ....................................................................................... 30 
10.2. Treatment Period ................................................................................................. 31 
10.3. End of Treatment ................................................................................................ 33 
10.4. Follow-up Period ................................................................................................. 33 
10.5. End of Study ......................................................................................................... 34 
10.6. Early Withdrawal of Subject(s) ......................................................................... 34 
10.7. Study Assessments ............................................................................................... 34 
11. SAFETY MONITORING AND REPORTING ..................................................... 38 
11.1. Adverse Events ..................................................................................................... 38 
11.2. Serious Adverse Events ....................................................................................... 38 
11.3. Emergency Un-blinding of Investigational Treatment .................................... 39 
11.4. Other Reportable Information ........................................................................... 40 
11.5. Special Warnings and Precautions .................................................................... 40 
11.6. Stopping Rules ..................................................................................................... 40 
11.7. Safety Oversight Committee (SOC) ................................................................... 40 
11.8. External Data and Safety Monitoring Board (DSMB) .................................... 40 
12. QUALITY CONTROL AND QUALITY ASSURANCE ..................................... 41 
12.1. Monitoring ............................................................................................................ 41 


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12.2. Audits .................................................................................................................... 41 
12.3. Data Management and Processing ..................................................................... 42 
13. STATISTICAL METHODS AND DATA ANALYSIS ........................................ 43 
13.1. Analysis Sets ......................................................................................................... 43 
13.2. Patient Demographics and Other Baseline Characteristics ............................ 43 
13.3. Treatments ........................................................................................................... 43 
13.4. Primary Objective ............................................................................................... 43 
13.5. Secondary Objectives .......................................................................................... 44 
13.6. Exploratory Objectives ....................................................................................... 47 
13.7. Interim Analysis ................................................................................................... 47 
13.8. Sample Size Calculation ...................................................................................... 47 
14. ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ............................. 48 
14.1. Regulatory and Ethical Compliance .................................................................. 48 
14.2. DUHS Institutional Review Board and DCI Cancer Protocol Committee .... 48 
14.3. Informed Consent ................................................................................................ 48 
14.4. Study Documentation .......................................................................................... 48 
14.5. Privacy, Confidentiality, and Data Storage ...................................................... 49 
14.6. Data and Safety Monitoring ............................................................................... 49 
14.7. Protocol Amendments ......................................................................................... 49 
14.8. Records Retention ............................................................................................... 49 
REFERENCES ................................................................................................................ 50 
15. APPENDICES .......................................................................................................... 55 
APPENDIX 1: EXCLUSIONARY MEDICATION ..................................................... 55 
APPENDIX 2: MEDICAL HISTORY .......................................................................... 60 
APPENDIX 3: PATIENT HEALTH QUESTIONNAIRE-9 ....................................... 64 
APPENDIX 4: GENERALIZED ANXIETY DISORDER .......................................... 65 
APPENDIX 5: SMOKING HISTORY QUESTIONNAIRE ....................................... 66 
APPENDIX 6: FAGERSTRÖM TEST OF NICOTINE DEPENDENCE ................. 68 
APPENDIX 7: RECENT SMOKING QUESTIONNAIRE ......................................... 69 
APPENDIX 8: SCREENING WEEK DIARY .............................................................. 70 
APPENDIX 9: SMOKING, MEDICATION USE, URGES AND MOOD & DIARY71 
APPENDIX 10: MEDICATION SIDE EFFECTS QUESTIONNAIRE .................... 76 
APPENDIX 11: MOOD AND PHYSICAL SYMPTOMS SCALE-2 ......................... 77 
APPENDIX 12: STATE-TRAIT ANXIETY INVENTORY ....................................... 78 
APPENDIX 13: CENTER FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE-R 80 
APPENDIX 14: MINNESOTA NICOTINE WITHDRAWAL SCALE .................... 82 
APPENDIX 15: PITTSBURGH SLEEP QUALITY INDEX ...................................... 83 
APPENDIX 16: BRIEF AGITATION MEASURE90 ................................................... 87 
APPENDIX 17: END OF TREATMENT FOLLOW-UP - SIDE EFFECTS QUESTIONNAIRE
 .................................................................................................................................... 88 
APPENDIX 18: SCOFF QUESTIONNAIRE (EATING DISORDER SCREEN)18.. 89 
APPENDIX 19: MOOD DISORDER QUESTIONNAIRE (MDQ)91 ......................... 90 
APPENDIX 20: MODIFIED MINI SCREEN (MMS) (PSYCHOTIC DISORDERS)17 
91 
APPENDIX 21: COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) . 92 
APPENDIX 22: BRIEF PSYCHIATRIC RATING SCALE (BPRS)93 ...................... 94 
APPENDIX 23: PERCEIVED STRESS SCALE (PSS-4)94 ......................................... 95 
APPENDIX 24: MODIFIED CIGARETTE EVALUATION QUESTIONNAIRE (MCEQ)95 96 
APPENDIX 25: DEMOGRAPHICS FORM ................................................................ 97 
APPENDIX 26: CONTACT INFORMATION FORM ............................................... 98 
APPENDIX 27: REVIEW OF SYSTEMS (ROS) ........................................................ 99 


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APPENDIX 28: ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT-C) 
101 
APPENDIX 29: 6 WEEK FOLLOW-UP SMOKING STATUS QUESTIONS ...... 102 
2. LIST OF ABBREVIATIONS 
 
AD 
 
Alzheimer’s Disease 
AE 
 
Adverse event 
AXSOME 
Axsome Therapeutics Incorporated  
AXS-05  
Novel fixed dose combination of Dextromethorphan-Bupropion (Axsome Therapeutics Inc.) 
AUDIT-C 
Alcohol Use Disorders Identification Test 
BID 
 
Twice a day 
BPRS 
 
Brief Psychiatric Rating Scale 
BUP 
 
Bupropion 
CBC 
 
Complete Blood Count 
CES-D  
Centers for Epidemiologic Studies - Depression Scale  
CO 
 
Carbon monoxide 
CPD 
 
Cigarettes per day 
CRC 
 
Clinical Research Coordinator  
CRS 
 
Clinical Research Specialist (Duke name for Research Assistant)  
CSC 
 
Center for Smoking Cessation  
C-SSRS  
Columbia-Suicide Severity Rating Scale 
DAST 
 
Drug Abuse Screening Test 
DSMB  
Data and Safety Monitoring Board 
DUHS  
Duke University Health System 
DXM 
 
Dextromethorphan 
FDA 
 
Food and Drug Administration  
FTND 
 
Fagerström Test of Nicotine Dependence 
GAD-7  
Generalized Anxiety Disorder 7-item Scale 
GCP 
 
Good Clinical Practice 
H&P 
 
History & Physical Exam 
HRPP 
 
Human Research Protections Program 
IR 
 
Immediate-release 
IRB 
 
Institutional Review Board  
mCEQ  
Modified Cigarette Evaluation Questionnaire 
MDQ 
 
Mood Disorder Questionnaire 
MMS 
 
Modified Mini Screen 
MNWS   
Minnesota Nicotine Withdrawal Symptoms Scale 
MPSS-2  
Mood and Physical Symptoms Scale 
NCI 
 
National Cancer Institute 
NIH 
 
National Institutes of Health  
SAE 
 
Serious Adverse Event 
WBC 
 
White Blood Cells 
MPSS  
Mood and Physical Symptoms Scale  
PHI 
 
Protected Health Information  
PHQ-9  
Patient Health Questionnaire-9  
PSQI 
 
Pittsburg Sleep Quality Index 
PSS-4  
Perceived Stress Scale-4 
ROS 
 
Review of Systems 
SAE 
 
Serious adverse event 
SR  
 
Sustained-release 
STAI  
 
State-Trait Anxiety Questionnaire 


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TRD 
 
Treatment Resistant Depression 
3. PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
3.1. 
PURPOSE 
Product Name: AXS-05 
Development Phase: Phase 2 
Protocol Title: A Randomized, Double-Blind 4-week Study to Evaluate the Impact of AXS-05 on Smoking Behavior  
This research study is designed with the purpose of evaluating a new drug, combination Dextromethorphan-
Bupropion (AXS-05), for its effect on smoking behavior.  
Primary Objective 
1. 
To evaluate the impact of AXS-05 compared to Bupropion (BUP) on change in smoking intensity from 
baseline to the 3-Week Follow-Up Visit. Smoking intensity refers to the total amount of smoke inhaled by the 
smoker and includes the number of cigarettes smoked per day. Smoking intensity will be assessed as a latent 
variable modeled through three predictive factors: 1. Salivary cotinine, which will be assessed at all study 
visits, 2. Expired carbon monoxide (CO) breath testing at all study visits and 3. Number of cigarettes smoked 
per day assessed via daily smoking diaries.  
Secondary Objectives (Smoking Behavior) 
2. 
To compare AXS-05 to BUP on smoking abstinence within a 7-day Abstinence Test conducted between the 3-
Week Follow-up and 4-Week Follow-up Study Visits. Smoking Abstinence will be assessed by self-report 
diaries and biochemically confirmed via expired CO and salivary cotinine.   
Secondary Objectives (Covariates and Potential Moderators) 
3. 
To assess specific baseline variables for an association with smoking behavior outcome, listed above. Baseline 
variables assessed will include age, gender, race, education, baseline nicotine dependence, stress, anxiety, 
depression, and self-efficacy. If a baseline variable is found to be associated with change in smoking behavior, 
it will be treated as a covariate in a secondary analysis of smoking behavior and assessed as a potential 
moderator of treatment effect.  
Secondary Objectives (Adherence, Side Effects, and Tolerance)  
4. 
To compare AXS-05 to BUP on adherence to self-administered drug through Medication Use diaries  
5. 
To compare AXS-05 to BUP on tolerability through weekly, open-ended survey to assess potential side 
effects.  
6. 
To compare AXS-05 to BUP on the incidence of adverse events or serious adverse events utilizing FDA 
accepted reporting guidelines on these outcomes.   
Secondary Objectives (Urinary Levels of DXM)  
7. 
To measure urine drug levels of Dextromethorphan (DXM) at weeks 1-4 and assess potential correlation of 
these levels with smoking behavior and side effects.  
Secondary Objectives (Potential Mediators)  
8. 
To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: 
smoking urges, withdrawal symptoms, smoking reward, stress, anxiety, depression, sleep disturbance, and 
agitation. 
9. 
To compare AXS-05 to BUP on change from baseline to weeks 1-4 Follow-up Visits on daily assessment of the 
following: urge frequency, urge severity, and irritability.  
 
 


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Hypotheses 
This protocol is hypothesis-supporting and hypothesis-testing.  
Primary Hypothesis 
1. 
Participants allocated to AXS-05 vs. BUP will demonstrate significant reduction in total smoking intensity 
from baseline to the 3-Week Follow up visit. Smoking intensity will be assessed as a latent variable modeled 
through 3 predictive factors: 1. Salivary cotinine, which will be assessed at all study visits. 2. Expired carbon 
monoxide (CO) breath testing at all study visits and 3. Number of cigarettes smoked per day will be verified 
objectively and salivary cotinine level. 
Secondary Hypotheses (Smoking Behavior) 
2. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate a significantly higher smoking abstinence 
rate within the 7-day Abstinence Test conducted between the 3 week Follow-up and 4 week Follow-up Study 
Visits. Smoking Abstinence will be assessed via self-reported smoking abstinence (not one puff of one 
cigarette) with biochemical confirmation via expired CO breath test and salivary cotinine.   
Secondary Hypotheses (Covariates and Potential Moderators) 
3. 
Potential baseline predictors of tobacco use will not be associated with smoking behavior outcomes listed in 
objectives 1-6; these predictors include age, gender, race, education, baseline nicotine dependence, stress, 
anxiety, depression, and self-efficacy.   
Secondary Hypotheses (Adherence, Side Effects, and Tolerance)  
4. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference on adherence to 
self-administered drug via Medication Use Diaries.  
5. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference in the incidence of 
side effects through weekly open-ended surveys on potential side effects. 
6. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference on adverse events 
or serious adverse events utilizing FDA accepted reporting guidelines on these outcomes.   
Secondary Hypotheses (Urinary Level of DXM)  
7. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate the following with regard to urinary drug 
levels at each medication assessment visit: 1. Relatively stable urinary drug levels of DXM (< 50% below or 
above the mean), 2. A majority of participants will show urinary DXM concentrations that are in the 
“expected therapeutic range” for tobacco dependence treatment (30 ng/ml), 3. There will be a correlation 
between DXM levels and smoking behavior outcomes (objective 2), 4. Urinary levels of DXM that are above 
the mean will not be associated with a higher incidence of side effects or adverse events (objectives 4-6) 
when added to BUP and compared to BUP alone.   
Secondary Hypotheses (Potential Mediators)  
8. 
Participants allocated to AXS-05 vs. BUP will demonstrate the following: 1. A significant reduction in smoking 
urges, withdrawal symptoms, stress, anxiety, depression, sleep disturbance, agitation from baseline to all 
four post-drug initiation time points, 2. The change in in smoking urges and withdrawal symptoms will be 
significantly associated with change in smoking behavior assessed through objective 2.   
9. 
Participants allocated to AXS-05 vs. BUP will demonstrate a significant reduction in urges and improvement in 
irritability from baseline to weeks 1-4 based on urges and irritability Diary entries.  
 
 


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3.2. 
 BACKGROUND AND SIGNIFICANCE 
1. The Study Therapy: The overarching goal of this proposal is to conduct preliminary testing of AXS-05 (a fixed dose 
combination of 105 mg of sustained-release (SR) Bupropion (BUP) and 45 mg of immediate-release (IR) 
Dextromethorphan (DM)) for its effect on smoking behavior. Dextromethorphan (DXM), a widely used over-the-
counter cough suppressant, crosses the blood-brain barrier easily. DXM has been shown to block α3β4 nicotinic 
acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors, is a serotonin and norepinephrine reuptake 
inhibitor, and is a sigma-1 receptor agonist.  Studies at our center have shown that administration of DXM leads to 
decreased self-administration of nicotine in nicotine-dependent rats in a dose-dependent manner (see #6 below in 
this section). DXM has not, however, been studied for its effect on tobacco use in humans.   
 
DXM, when taken alone (e.g. when it is used as a cough suppressant), would not be expected to be useful for 
treatment of nicotine dependence in humans. Therapeutic concentrations of DXM are required to bind the receptors 
that impact neurotransmitters that are important in the treatment of nicotine dependence; however, it is not 
possible to attain these concentrations of DXM in humans when it is dosed as a single agent because of its rapid 
metabolism via CYP2D6. Because approximately 95% of DXM that is ingested is quickly metabolized into dextrorphan 
via the CYP2D6 pathway, plasma concentrations of DXM are negligible when it is administered alone.  The metabolite 
dextrorphan is quickly glucurodinated and therefore does not easily cross the blood-brain barrier and thus would not 
be expected to have a meaningful impact on nicotine self-administration in humans. An innovative approach to attain 
therapeutic concentrations of DXM is to co-administer it with an inhibitor of its metabolism. Such an approach would 
allow for attainment of plasma concentrations that have been shown to result in the binding of neural receptors that 
impact nicotine self-administration (See #6 below in this section).  
 
Bupropion (BUP) is a well-characterized, FDA approved medication for smoking cessation that has also been 
shown to inhibit the metabolism of DXM. When various doses of BUP – including doses that are commonly 
prescribed for smoking cessation (e.g. 150 mg or less) – are co-administered with DXM to healthy volunteers, a 
significant increase in DXM plasma levels is observed (See Investigators Brochure Version 4.0 [IND 129633] Section 
5.1.1: AXS-05 (Bupropion and Dextromethorphan Pharmacokinetics). This finding, together with the finding that 
similar DXM levels reduce nicotine self-administration in nicotine-dependent rats, suggests that it may be possible to 
develop a drug product that combines safe, commonly used doses of DXM and BUP that would be well-tolerated and 
result in a reduction in smoking behavior in humans.  
Currently, the pharmaceutical development company Axsome Therapeutics Inc. (Axsome) is developing and testing 
an oral fixed-dose combination 45 mg IR DXM with 105 mg SR BUP to achieve therapeutic concentrations of DXM. 
The BUP in this combination serves to increase the bioavailability of DXM, and act as a norepinephrine and dopamine 
reuptake inhibitor and a nicotinic acetylcholine receptor antagonist. This investigational drug product has been 
designated with the name “AXS-05,” and for clarity, we will refer to it as such in this protocol. In three completed 
Phase I trials and two ongoing Phase II/III trials sponsored by Axsome, AXS-05 has been found to be generally safe 
and well-tolerated in the completed three Phase 1 studies and the adverse event profile of AXS-05 was similar to that 
of BUP alone. AXS-05 is currently being evaluated for efficacy and safety in “adequate and well-controlled 
registration trials in treatment-resistant depression and agitation associated with Alzheimer’s disease (see below). 
Thus far, AXS-05 has not been tested for its effect on tobacco use in humans; furthermore, to our knowledge, DXM 
has not been studied in combination with BUP or any other CYP2D6 inhibitor (e.g. quinidine) for its impact on 
tobacco use in humans.  
2.  The disease population:  This study evaluates individuals with tobacco dependence. Tobacco use is the number 
one cause of preventable morbidity and mortality in the US1,2. It causes 480,000 deaths per year and is the cause of 
death in approximately two-thirds of all smokers2.   
3.  The clinically unmet need for this type of supportive care:  Pharmacotherapy is the primary treatment used by 
people who smoke to quit smoking. Approximately 29.9% of all smokers attempt to quit smoking with the use of a 


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medication3. Currently, there are seven FDA approved smoking cessation medications: varenicline, bupropion, 
nicotine patch, gum, lozenge, inhaler, and nasal spray4. These FDA approved medications roughly double the chances 
of quitting during any given quit attempt; efficacy vs. placebo of RR=1.7 (nicotine gum), RR=1.8 (bupropion) to RR=2.4 
(varenicline)5. Development of a new medication class with oral administration, low incidence of side effects, and 
greater efficacy than that of bupropion has the potential for high-level adoption and large-scale population impact.    
4.  Why the stated objectives of the research are important:  This study is designed to produce evidence that AXS-05 
leads to significant reduction in smoking compared to a matched dose of BUP through analysis of daily smoking 
diaries and leveraging the statistical advantages of repeated measures analysis. Additionally, the study is designed to 
assess measures which predict smoking abstinence: the 7 Day Smoking Abstinence Test 6. The study is designed to 
closely monitor drug adherence through the diaries, assess side effects of medications, and assess the impact of 
urine drug levels on smoking behavior and side effects. Finally, an assessment of mechanism is provided to estimate 
the impacts of known physiologic activities. These inquiries are designed to demonstrate that AXS-05 has an impact 
on smoking behavior beyond that of BUP, a well-established and FDA approved tobacco dependence treatment. The 
study is designed to assess changes (reductions) in smoking behavior that may occur in current smokers who use 
AXS-05. If results are positive, the study outcomes are designed to guide further development of AXS-05 as a smoking 
cessation treatment.  
5.  The rationale for performing this research: The overarching rationale for performing this research is the study’s 
high potential for future impact. If AXS-05 is found to be a safe and effective treatment and is approved as an aid to 
smoking cessation, it could be made available to thousands of smokers through Axsome’s access to large-scale drug 
production and capacity for national distribution. This long-term potential for production and distribution means that 
positive study findings may lead to further development of this potential treatment and, if successful, a reduction in 
smoking rates in the US and abroad.   
6.  Citations for existing literature that supports the rationale for performing this research: Dextromethorphan 
Reduces Nicotine Self-Administration in Rats7.  Design: Young adult female rats were fitted with jugular IV catheters 
and trained to self-administer a nicotine infusion dose of 0.03 mg/kg/infusion. Then, in a dose-effect function study, 
oral DXM was administered over five doses ranging from 0 to 30 mg/kg. Results: DXM administration significantly 
decreased nicotine self-administration in a dose-dependent manner with maximal effect seen at 30 mg/kg (p<.0005) 
(Figure 2). Throughout varied doses, motor function and food intake showed no significant changes, suggesting low 
toxicity. Relevance: This study showed that administration of DXM leads to decreased nicotine self-administration in 
rats, suggesting that we may observe a similar finding in humans if we are able to obtain similar plasma 
concentrations of DXM.   
7.  Published and unpublished clinical data, if any, that supports the conduct of this research: Studies completed by 
Axsome on AXS-05, described in the Investigators Brochure Version 4.0 [IND 129633]  Section 5.1.1: AXS-05 
(Bupropion and Dextromethorphan) Pharmacokinetics) provide evidence of the following:  1. Administration of 
combination AXS-05 results in a significant increase in plasma DXM levels, 2. BUP-inhibited metabolism of DXM 
extends DXM half-life sufficiently (from 2 hours to 20 hours) to allow for twice daily dosing of AXS-05 with stable 
plasma levels. Furthermore, additional studies, found that DXM co-administered with the metabolic inhibitor 
quinidine results in a reduction of depressive symptoms in patients with treatment-resistant depression8 and DXM 
co-administered with the metabolic inhibitor quinidine results in reduction of agitation symptoms in individuals with 
Alzheimer’s type dementia9.   
8.  How conclusions derived from this research will be used:  Results from this pilot study will be used as supporting 
evidence for the design of a fully powered, randomized controlled trial on the use of AXS-05 as a treatment for 
tobacco dependence.   
9. Previous Human Experience with the Proposed Dose: The proposed doses to be used in this study are as follows: 
AXS-05 (105 mg BUP/45 mg DXM), twice daily and 105mg BUP SR, twice daily. The proposed dose of AXS-05 for this 


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study is identical to the dose used in Study AXS-05-301 during the six-week double-blind treatment period and used 
in Study AXS-05-AD-301 used for following the titration for five consecutive weeks (Days 8 to 43) (see Investigator’s 
Brochure Version 4.0 [IND 129633]  Section 5.5.1: AXS-05 (Bupropion and Dextromethorphan) Clinical Safety 
Experience). However, in the study, patients will be exposed to either AXS-05 or 105 mg BUP SR for only 28 days. 
3.3. 
 DESIGN AND PROCEDURE  
Non-Treatment Study: This study is designed to assess changes in smoking behavior in smokers who use AXS-05 
compared to those who use bupropion alone. 
Research Design and Procedures Overview: The proposed study is a Phase II double-blind, randomized active-
controlled 4-week trial of approximately 60 daily smokers willing to abstain from smoking for 1 week. We will 
consent up to 150 individuals and randomize up to 70 individuals into treatment arms. The goal is to achieve 
approximately 60 randomized participants that complete at least 3 weeks of assessments (assessments through Visit 
4). Participants will be randomized with 1:1 allocation to AXS-05 (45 mg Immediate Release DXM + 105 mg Sustained 
Release BUP) vs. 105 mg Sustained Release BUP, twice daily (BID). Subjects will be instructed to only take 1 tablet for 
the first 3 days. Subjects not completing three weeks of assessments will be replaced to ensure that 60 randomized 
patients (30 per group) complete the study through the 3-week Follow-up Assessment Visit (Visit 4).  
The dose of AXS-05 to be used in the study is identical to the one being used in the ongoing clinical trials in TRD and 
Agitation in patients with Alzheimer’s Disease.  DXM and BUP doses are FDA approved for other indications and have 
been found to be safe and generally well-tolerated in combination (as AXS-05) in three Phase I studies to date. 
Medications will be continued for four weeks in each group. Laboratory testing, including expired breath CO and 
salivary cotinine, will occur at the Baseline Visit and each visit thereafter to objectively assess the number of 
cigarettes smoked per day in addition to daily smoking diaries. Additional testing on smoking behavior will include 
abstinence testing during the 7-day Smoking Abstinence Test at the 4-week Follow-up Assessment Visit. Potential 
side effects of AXS-05 and BUP alone will be assessed through repeated survey administration with open-ended 
questions and spontaneous report. Adherence to drug use will be assessed through Medication Use Diaries collected 
at each study visit. Urine drug levels will be collected Visits 2-5 to allow for correlation of urine drug levels to the 
number of cigarettes smoked per day (Cotinine, CO) and side effects. Pre-post drug initiation changes in smoking 
urges, withdrawal, stress, depression, anxiety, motivation and sleep quality will be assessed as potential mediators of 
effect on smoking behavior.   
 
 
3.4. 
SELECTION OF SUBJECTS 
Inclusion Criteria:  
1. 
Age 18 years or above  
2. 
Daily smoker using 10 or more cigarettes per day10  
3. 
Willing to be smoke-free for 7 days 
4. 
Is able to provide written informed consent (in English) to participate in the study and able to understand the 
procedures and study requirements.  
5. 
Is willing to voluntarily sign and date an informed consent form that is approved by an institutional review 
board before the conduct of any study procedure. 
6. 
If female and of childbearing potential, is willing to use medically acceptable contraceptive measures for the 
duration of the study. Acceptable methods of contraception include (1) surgical sterilization (such as tubal 
ligation or hysterectomy, (2) approved hormonal contraceptives (such as birth control pills, patches, implants 
or injections), (3) barrier methods (such as condom or diaphragm) used with a spermicide, or (4) an 
intrauterine device (IUD). Contraceptive measures such as rhythm method or Plan B ™, sold for emergency 
use after unprotected sex, are not acceptable methods for routine use. 


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Exclusion Criteria:  
1. 
Current use of a smoking cessation medication (e.g. nicotine replacement, varenicline, bupropion)  
2. 
Current use of tobacco product other than cigarettes (e.g. e-cigarettes, smokeless tobacco) 
3. 
Answer > 0 on suicidality question of Patient Health Questionnaire (PHQ-9) Depression Scale11 
4. 
Active alcohol use disorder or hazardous drinking. This will be screened with the AUDIT-C, and positive scores 
(4 or greater for  men and 3 or greater for women12) will result in study clinician assessment and discretion.  
5. 
Use of illicit drugs in the last month (marijuana, cocaine, opiates, benzodiazepines, methamphetamine)  
6. 
Severe symptomatic depression and or anxiety (study physician discretion) 
7. 
Diagnosis of bipolar disorder, schizophrenia, PTSD and or adult ADHD  
8. 
GAD-7 Anxiety scale of 15 or higher13 
9. 
Chronic medical illness including diabetes with the use of insulin, Hemoglobin A1c > 7 (study physician 
discretion), heart disease diagnosed by angiogram, COPD diagnosed by pulmonary function testing and 
requiring an oxygen supply 
10. 
Specific medications (Appendix 1)  
11. 
Abnormal finding on physical exam (study physician discretion)  
12. 
Expired breath carbon monoxide < 10  
13. 
Abnormal EKG (study physician discretion) 
14. 
Abnormal Complete Blood Count, Comprehensive Metabolic Panel, Urine Hgb AIC (study physician 
discretion) 
15. 
Positive Urine Pregnancy Test (women of child bearing potential only) (QuickVue One Step hCG)14 
16. 
Positive Urine Toxicology-5 Screen (methamphetamine, cocaine, opiates, benzodiazepines, THC)15 
17. 
Contraindication to the use of bupropion including seizure disorder or conditions that increase the risk of 
seizure (including bulimia and/or anorexia nervosa, CNS tumor, severe stroke, abrupt withdrawal from 
benzodiazepines or alcohol). 
18. 
Unstable hypertension (Blood pressure > 160/100) 
19. 
Hepatic impairment as defined by ALT or AST levels greater than 2 times the upper limit of normal. 
 
Use of Inclusion/Exclusion Criteria: The primary considerations for the use of inclusion/exclusion criteria include 
consent (English, age), patient safety (illness, medications, blood tests, pregnancy), and generalizability (willingness 
to quit, cigarette use, drug and alcohol use, psychiatric illness).  
Assessment and Follow-up of Specific Exclusion Criteria: 
If a participant is excluded based on criteria above, the study medical provider will further assess the exclusion 
through medical interview as needed. If this interview reveals a safety issue for the excluded individual, the medical 
provider will send a letter to the excluded individual’s primary care provider or seek immediate medical assistance if 
necessary.  
Management of specific exclusion criteria are detailed below:  
Generalized Anxiety Disorder will be assess using the GAD-713. Scores of 15 or higher indicate severe anxiety, and will 
be exclusionary. If a potential participant scores above a 15 they will be referred to their PCP for further follow-up. In 


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addition, the study Physician or PA will generate a letter to the excluded individuals PCP to notify them of the results. 
Suicidality will be assessed using the PHQ-911. A score of >0 on question 9 of the PHQ-9 (“Thoughts that you would be 
better off dead or hurting yourself in some way”) will be exclusionary. If a participant scores >0 on question 9, the 
Physician or PA will be notified immediately for further clinical assessment and appropriate referral and follow-up.  
The Audit-C will be used to assess for alcohol use disorder12 during the phone screen. A score of >4 for men or >3 for 
women will be considered positive, and the potential participant will be excluded from the study.  
Bipolar Disorder will be assessed using the Mood Disorder Questionnaire (MDQ)16. A positive screen involves 
answering “Yes” to 7 or more of the 13 items in section 1, “Yes” to section 2, and “Moderate Problem” or “Serious 
Problem” in section 3. A positive screen will result in further assessment by the Physician or PA and appropriate 
referral and follow-up. If needed, the individual will be given information for the Duke Mental Health Services, 
including their phone number (919-684-0100).  
Psychotic Disorders will be assessed using the Modified Mini Screen (MMS) Section C17. If the potential participant 
states “Yes” to any of the questions, or there is concern for psychotic disorder in the clinician’s judgement, the 
potential participant will be excluded from the study. The study Physician or PA will assess for appropriate follow-up 
and referral. If needed, the individual will be given information for the Duke Mental Health Services, including their 
phone number (919-684-0100). 
Anorexia and Bulimia will be assessed using the SCOFF Questionnaire18. An answer of “yes” to two or more questions 
will be considered a positive screen. A positive screen will result in further assessment by the Physician or PA and 
appropriate referral and follow-up. If needed, the participant will be given information for the Duke Center for Eating 
Disorders, including their phone number (919-668-0397). 
A history of seizure disorder will be assessed through the Medical History form (Appendix 2) in two ways. First, 
participants will ask if they have a diagnosis of a seizure disorder. If the potential participant reports “Yes” to a 
diagnosis of seizure disorder, they will be excluded. Secondly, potential participants will be asked if they have ever 
experienced a seizure or seizure-like activity. If the individual reports “Yes,” the study Physician or PA will further 
assess the event and provide additional follow-up and referrals as necessary.  In addition, history of conditions that 
increase the risk for seizure will be assessed through the Medical History form (Appendix 2)  
Potential participants will be assessed for medications that lower seizure threshold via a medication exclusion list, 
found in Appendix 1. 
Assessment of Potential Side Effects throughout Study 
During the course of the study, participants will be assessed at each visit on the following parameters to assess the 
potential for medication side effects: suicidality, psychosis, depression, anxiety, sleep quality, agitation, as well as an 
open-ended question on potential medication side effects.  
Suicidality: A study drug, Bupropion, can increase the risk of suicidality, so suicidality will be assess at each study visit. 
Participants will be assess for suicidality using the PHQ-9 question 9 (Appendix 3) at each visit after initiation of the 
study drug. If a participant scores >0 on this question, the study clinician will administer the Columbia Suicide 
Severity Rating Scale (C-SSRS). The C-SSRS assesses suicidal ideation, intensity of ideation, and suicidal behavior.  The 
results of the C-SSRS will be used for further clinical assessment and follow-up as needed. This follow-up will be 
based on a medical assessment of the situation, and may include a referral to mental health services or immediate 
psychiatric evaluation in the Emergency Department if needed. 
Psychosis: Participants will be assessed for psychotic disorders using the MMS Section C (Appendix 20) at each visit 
after initiation of the study drug. If a participant answers “Yes” to any of the items on the MMS Section C, a study 
clinician will administer the Brief Psychiatric Rating Scale (BPRS) (Appendix 22). This will be used for further clinical 
assessment and follow-up as needed. The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered instrument 


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used for assessing positive, negative and affective symptoms for psychotic disorders over 18 symptom constructs.  A 
study drug, Bupropion, can cause psychosis, so this assessment will be used to assess for emerging or worsening 
symptoms of psychosis. 
Depression: The Center for Epidemiologic Studies Depression Scale-Revised (CES-D-R) (Appendix 13) is a 20 item scale 
that asks participants to rate how often they have had symptoms of depression (following the DSM-V). A study drug, 
Bupropion, can cause depressive symptoms, so this assessment will be used to assess for emerging or worsening 
symptoms of depression. The score will be reviewed by the study clinician, and appropriate follow-up and referral 
will be initiated as needed.  
Anxiety: The State-Trait Anxiety Inventory (STAI) (Appendix 12) is a 40 item introspective measure developed to 
assess both trait and state anxiety. A study drug, Bupropion, can cause anxiety, so this assessment will be used to 
assess for emerging or worsening symptoms of anxiety. The study clinician will review the results of the measure and 
arrange appropriate follow-up and referral as needed. 
Sleep Quality: The Pittsburgh Sleep Quality Index (PSQI) (Appendix 15) is a 19-item scale that was designed to assess 
the quality and patterns of sleep of adults. A study drug, Bupropion, can cause sleep disturbance, so this assessment 
will be used to assess for worsening sleep quality.  This measure will be administered at each study visit to assess for 
changes in sleep quality.  
Agitation: The Brief Agitation Measure (Appendix 16) is a 3-item scale designed to assess a participant’s agitation 
level. A study drug, Bupropion, can cause agitation, so this assessment will be used to assess for emerging or 
worsening symptoms of agitation. The study clinician will review this measure and provide further clinical assessment 
and follow-up as needed. 
 
3.5. 
DURATION OF STUDY  
TIMELINE: Study activities will occur over approximately 14-month period. Two and a half months are allocated for 
hiring and training staff, IRB approval, and development of procedures. Approximately nine months are allocated for 
recruitment of 150 consented subjects and enrollment of 670 subjects who smoke to achieve 60 randomized subjects 
who complete at least three weeks of assessment (Visit 4).  Approximately one month is allocated to complete the 
Final Assessment Visits and approximately one and a half months are allocated for analyses and manuscript 
preparation (Table 1).  
Table 1: Month Timeline for Grant-Funded Period 
3.6. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
A detailed Data Analysis is provided in Section 13.  A summary of data analysis procedures includes the following: 
Multilevel Modeling: Given repeated observations across multiple individuals, many of the analyses in this study will 
be derived from multilevel modeling (MLM). Missing Data: Missing data will be examined to determine whether 
missingness is systematic (i.e. associated with individual baseline differences or time-related changes in observed 
variables). An intent-to-treat approach in which subjects lost to follow-up will be counted as non-abstinent will also 
be used to analyze univariate outcomes. An alpha criterion of 0.05 will be used in all comparisons. Analysis of 
Study Activities  
14 Months 
Stage 1 
2.5 months 
Stage 2  
9 months 
Stage 3 
1 month 
Stage 4 
1.5 
months 
Staff Hiring and Training  
 
 
 
 
IRB/Data Base Build  
 
 
 
 
Procedure Development 
 
 
 
 
Recruitment + Enrollment  
 
 
 
 
Assessment Visits  
 
 
 
 
Analysis and Publication  
 
 
 
 


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Primary Outcome:  The primary study outcome is an assessment in change in smoking intensity from baseline to 
Week-3 Follow-Up Visit in AXS-05 vs. BUP groups with smoking intensity modeled as a latent variable through 
predictor variables of 1. Salivary Cotinine, 2. Carbon Monoxide Breath Test and 3. Number of cigarettes smoked per 
day. To enhance power for our primary outcomes, we will use repeated measures analysis to capture daily entry of 
the number of cigarettes smoked per day in smoking diaries. Secondary abstinence outcomes: Here we will include 
change in the number of cigarettes smoked per day from baseline to all Follow-up Visits (Visits 2-5), with 
confirmation of self-report through expired CO and salivary cotinine testing. We will also assess change in CO and 
cotinine as independent outcomes and abstinence rates through the 7 day Abstinence Test. Assessment of potential 
moderators of primary effect: The following constructs will be assessed as potential predictors of abstinence: 
demographics (age, gender, race, education), smoking history and heaviness, prior quit attempts, dependence 
(FTND), urge rating (MPSS), depression (PHQ-9), anxiety (GAD-7), alcohol use (AUDIT-C), drug use (DAST), stress (PSS-
4), and self-efficacy questions. Assessment of potential mediators of primary effect: The following constructs will be 
assessed to determine whether assignment to the study group is associated with change pre- and post-treatment: 
urge rating (MPSS), depression (CES-D), anxiety (STAI), withdrawal symptoms (MNWS), stress (PSS-4), sleep quality 
(PSQI) and agitation (BAM).). Sample Size Calculation: Total sample size required to show differences in primary 
outcomes between AXS-05 vs. BUP with 10% downward adjustment in study group outcomes for possibility of 
unexpectedly poor outcomes is N = 60 (completed patients). Approximately 66 subjects may be enrolled to achieve 
60 randomized subjects who complete at least three weeks of assessments (Visit 4).     
All analyses will be performed on the Intent-to-Treat group that is defined as all subjects randomized and all 
replacement subjects, if applicable. 
   
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. STUDY SCHEMA  
 
 


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5. BACKGROUND AND SIGNIFICANCE 
5.1. 
STUDY CONDITION 
1.  Incidence, prevalence, and main causes and concerns:  
Tobacco use is the number one cause of preventable morbidity and mortality in the US1,2. It causes 480,000 deaths 
per year and is the cause of death in approximately two-thirds of all people who smoke2. Since the 1964 Surgeon 
General’s Report on the health effects of smoking19, US smoking rates have fallen from 42.2%19 to 15.1%20. Many 
smokers who have been able to quit, have already done so using available treatments. This means that today’s 
remaining smokers who are unable to quit are an increasingly treatment-resistant population4. Abstinence rates for 
unassisted quit attempts are less than 5%4 and new, successful treatment approaches for the current population of 
smokers are urgently needed.  
2.  The current therapeutic or management options:   
Pharmacotherapy is the primary smoking cessation treatment used by people who smoke, with 29.9% of smokers 
attempting to quit smoking with the use of a medication3. Currently, there are seven FDA approved smoking 
cessation medications including varenicline, bupropion, nicotine patch, gum, lozenge, inhaler, and nasal spray4. These 
approved medications roughly double the chances of quitting during any given quit attempt; efficacy vs. placebo of 
RR=1.7 (nicotine gum), RR=1.8 (bupropion) to RR=2.4 (varenicline)5. Additionally, AXS-05 represents a new drug class 
with effects on depression and agitation (below) – constructs which are known to play a role maintaining tobacco use 
behavior. The development of a new class of drug which impacts tobacco use through reduction of depression 
symptoms and agitation has the potential to impact a large population of smokers who are unable to quit due to 
these affective challenges. 
3.  Explanation of how/why the current options are inadequate: 
The relatively low dosing of BUP and DXM used in AXS-05 (DXM IR 45 mg/BUP SR 105mg) suggests the potential 
advent of a smoking cessation medication with a low side effect profile and high tolerability. Side effects strongly 
predict adherence to smoking cessation medications and are highly predictive of smoking cessation outcomes. In one 
study, smokers adherent to medication showed 1.8 times higher abstinence (p = 0.0001) than non-adherent 
smokers21. Unfortunately, the most commonly prescribed FDA approved smoking cessation medications (Varenicline 
and Nicotine Patch) have fairly high incidence of side effects (bupropion, nicotine lozenge and gum are better 
tolerated). One study comparing varenicline vs. placebo found the following side effect incidence rates: nausea 
(28.1% vs. 8.4%), headache (15.5% vs. 12.2%), vivid dreams (10.3% versus 5.5%)22. A meta-analysis23 (N > 177,000) on 
side effects from nicotine replacement (the most commonly used smoking cessation medication) showed the 
following side effect rates vs. placebo (all p < 0.001): Headache (9.7% vs. 4.7), nausea (8.5% vs. 5.1%), insomnia 
(11.4% vs. 8.0%), skin irritation – patch (19.5% vs. 6.9%)23. A study (N=225)24 on nicotine patch adherence (daily use 
for 28 days), found that 64.7% of participants were non-adherent and stopped regular use (30% forgot to use it, 15% 
had side effects, 10% relapsed, 7% financial challenges). A study (N=662) on nicotine gum adherence (use of 75% of 
prescribed gum) showed that 73.4% were non-adherent, most frequently due to forgetting to use the gum25. A study 
on Bupropion 150 mg SR showed that the side effects of insomnia, headache, and nausea are most common, but 
discontinuation of Bupropion 150 mg SR dosing due to side effects was only 7%26. Development of a new medication 
class with oral administration, efficacy beyond that of bupropion, and a low incidence of side effects has the 
potential for high-level adoption and large scale population impact. 
4.  Any relevant treatment issues or controversies:  
AXS-05 has not been used for treatment of tobacco dependence. As such, there are no treatment issues or 
controversies that need to be explored. Because the drug is new for this indication, it is unknown whether the drug 
will lead to a reduction in smoking in humans. AXS-05 was found to be safe and generally well-tolerated in three 
Phase 1 trials conducted in over 100 subjects. To date, in two ongoing “adequate and well-controlled” clinical trials in 


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treatment resistant depression and agitation associated with dementia of the Alzheimer’s type blinded study 
medication (AXS-05, BUP or placebo) has been well tolerated. Smoking is a behavior and there is no reason to think 
that side effects of AXS-05 will be different in smokers than those subjects enrolled in the three completed Phase 1 
studies.  
5. Other concerns related to quality of life or treatment deviation due to study condition:  
AXS-05 is being used to reduce smoking behavior in current smokers. Smoking is a health hazard, and reduction in 
smoking is widely known to have health benefits. There is no treatment deviation due to study condition.    
5.2. 
Study Drug 
5.2.1. 
TYPE OF DRUG  
AXS-05 as used in this study is a fixed-dose combination of dextromethorphan (DXM) immediate release (IR) 45 mg 
and bupropion (BUP) sustained release (SR) 105 mg taken two times daily. Either AXS-05 or BUP (SR) will be dosed 
twice daily (1 tablet for the first 3 days) for 28 days (4 weeks). 
AXS-05 (AXS-05) (STUDY DRUG)  
Information on drug structure, formulation, and manufacturing may be found within the Investigators Brochure 
Version 4.0 [IND 129633] Section 3: Chemistry and Pharmaceutical Information included in this application. 
BUPROPION SR 105 mg (CONTROL DRUG)  
Information on drug structure, formulation, and manufacturing may be found within Investigators Brochure Version 
4.0 [IND 129633] Section 3: Chemistry and Pharmaceutical Information included in this application.  
5.2.2. 
DRUG MECHANISM OF ACTION 
Dextromethorphan Mechanism of Action:  
DXM is a widely used over-the-counter cough 
suppressant with minimal side effects at 
recommended doses (5-15 mg every 2 hours or 30-60 
mg twice per day)27. DXM easily crosses the blood-
brain barrier28. In blood, 65% of DXM is bound to 
carrier proteins, with 35% of DXM in free form; a 
similar concentration of free DXM (30%) is found in 
urine and cerebral spinal fluid (CSF)29. Once DXM is in 
the CSF at sufficient concentrations, it binds to the 
following receptors: α3β4 nicotinic acetylcholine 
receptor (nAChR) is found in the presynaptic terminals 
of neo-cortical neurons that secrete norepinephrine as 
well as other sites30,31. DXM is an efficient α3β4 nAChR 
antagonist, acting independently of the nicotine 
binding site, providing robust (non-competitive) 
inhibition of the receptor32. The α3β4 nAChR and DXM binding of α3β4 nAChR are associated with reduction in 
physical withdrawal symptoms reduction in nicotine reward-based behavior33, 34;  Sigma-1 receptor is found mostly 
within the cerebellum, brainstem, neocortex, striatum, and hippocampus35.  DXM is a Sigma-1 agonist, as seen with 
cough suppression through binding of sigma-1 in the medullary cough center36,37, but does not have significant 
activity at other opioid receptors38,39. Therapeutic effects of DXM activation of Sigma-1 include an anticonvulsant 
effect37,40, significant neuroprotective effects in degenerative brain disease41,42, and antidepressant effects in 
animals43; N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that, when activated, release 
glutamate (a fast acting excitatory neurotransmitter)44. DXM binds deep inside the NMDA ion channel as a non-
Figure 1: Dextromethorphan Mechanism of Action 


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competitive receptor antagonist45. Potentially important for addiction recovery, NMDA receptor activation is involved 
in neuroplasticity, and activates neurons involved in cue-based learning and memory formation46,47,48; Serotonin is a 
monoamine with substantial effect on regulation of mood in humans. Increasing synaptic serotonin by using a 
serotonin reuptake inhibitor is the primary mechanism of many antidepressants. There are 14 known serotonin 
transporters that control serotonin levels at various sites in the brain49. DXM is a non-selective serotonin transporter 
reuptake inhibitor (inhibits all known serotonin transporters) leading to increased serotonin levels in the brain50 and 
co-administration of DXM and  the metabolic inhibitor quinidine has previously been shown to reduce depressive 
symptoms in treatment resistant depression, agitation associated with Alzheimer’s  type dementia, and 
pseudobulbar affect (PBA); Norepinephrine - During nicotine withdrawal, an aspect of the withdrawal syndrome is 
related to low levels of synaptic norepinephrine51. Low norepinephrine is associated with poor attentional control, 
difficulty concentrating, and lack of productivity52. DXM is a norepinephrine reuptake inhibitor, and increases 
norepinephrine levels in the brain53. The following are DXM concentrations within the CSF required to activate each 
receptor: α3β4 nAChR = IC50 of 700nM54; Sigma-1 receptor = 400nM53; NMDA  Concentrations of DXM necessary for 
NMDA blockade = 780 nM55.  Serotonin receptors = 240 nM56 norepinephrine (α1D receptor) 830 nM29. 
Unfortunately, DXM at FDA approved doses leads to CSF concentrations (4-600nM) that only activate Serotonin and 
Sigma-1 receptors, but not α3β4 nAChR, NMDA, or α1D, which appear to be critical to its role in reducing nicotine 
self-administration. Lower levels of DXM in the brain are a result of DXM metabolism (Figure 1)57. DXM is metabolized 
via the CYP2D6 pathway (Cytochrome p450) to dextrorphan. DXM metabolism occurs rapidly after ingestion during 
the first pass through the liver, resulting in roughly 95% of DXM being metabolized into dextrorphan. Dextrorphan 
does not easily pass the blood-brain barrier and shows minimal activity in the brain. One way to greatly increase the 
CSF concentration and central activity of DXM is to administer DXM with a CYP2D6 inhibitor. Bupropion is a potent 
CYP2D6 inhibitor at low (non-therapeutic) doses58. Interestingly, 5-10% of Caucasians have a homozygous deficiency 
of the CYP2D6 enzyme and metabolize DXM to Dextrorphan more slowly, showing higher CSF levels of DXM59.  
Bupropion Mechanism of Action: 
Bupropion is an antidepressant medication that is FDA approved for use in smoking cessation under the trade name 
Zyban, referring to the 150 mg sustained release formulation taken two times daily. Bupropion is thought to help 
with nicotine dependence through several mechanisms. Bupropion is a selective norepinephrine and dopamine 
reuptake inhibitor that increases synaptic levels of norepinephrine and dopamine, but not synaptic levels of 
serotonin60.  
5.2.3. 
RATIONALE FOR USE OF STUDY DRUG IN THIS PARTICULAR SUPPORTIVE 
CARE CONTEXT 
Rational for using combination AXS-05 in Human Smokers: AXS-05 has not been tested for its effect on tobacco use. 
AXS-05 shows considerable promise as a potential smoking cessation treatment of from a pharmacologic perspective 
of receptor binding. Additionally, AXS-05 is being evaluated in clinical trials for treatment-resistant depression and 
agitation associated with Alzheimer’s type dementia and both depression and agitation have been shown to be 
associated with relapse in smokers. AXS-05 was safe and well-tolerated in 3 Phase 1 studies which enrolled over 100 
subjects and a similar side effect to that of BUP alone. DXM has been shown to reduce nicotine self-administration in 
nicotine-dependent rats. Thus, it is reasonable to assess AXS-05 in smokers. If findings are positive, that is, if we see a 
significant reduction in smoking in AXS-05 vs. BUP alone, we will proceed with a fully powered, randomized smoking 
cessation trial on AXS-05 as a treatment for smokers who would like to quit smoking. If a fully powered smoking 
cessation trial were found to have positive results, Duke and Axsome would be well positioned to proceed with steps 
toward FDA approval of AXS-05 as a treatment for tobacco dependence.  
The proposed dose and duration of use of AXS-05 for this study, is supported by other ongoing studies (Section 5.2.5 
Clinical Experience).    


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5.2.4. 
 PRE-CLINICAL EXPERIENCE OF STUDY DRUG 
Pre-clinical experience (animal studies) have been conducted on DXM and BUP (the components of AXS-05).  A 
description of these pre-clinical studies on DXM and BUP may be found within the Investigators Brochure Version 4.0 
[IND 129633] Section 4: Nonclinical Studies included in this application. This includes information on non-clinical 
pharmacology, pharmacokinetics, toxicology, carcinogenicity, genetic toxicity, and reproductive and developmental 
toxicity.  
Furthermore, a 2016 study at our center demonstrated that oral DXM administration significantly decreased nicotine 
self-administration of rats in a dose-dependent manner. Across the DXM dosing, which ranged from 0 to 30mg/kg, 
motor function and food intake did not show significant changes.   
5.2.5. 
 CLINICAL EXPERIENCE  
Clinical experience with AXS-05 and with the control drug (BUP) may be found within the Investigators Brochure 
Version 4.0 [IND 129633] Section 5: Effects in Humans, included in this application.  This includes information on 
human pharmacokinetics, distribution, metabolism, elimination, drug interactions, clinical efficacy, and clinical 
safety. 
AXS-05 has been found to be safe and generally well-tolerated in three completed Phase 1 trials which enrolled over 
100 healthy volunteers. In two ongoing blinded “adequate and well-controlled” clinical trials, blinded study 
medication was well tolerated (AXS-05, BUP or placebo). AXS-05 is being evaluated under IND124813 for treatment 
resistant depression (ClinicalTrials.gov Identifier: NCT02741791) and under IND129633 for Agitation associated with 
Alzheimer’s Disease (ClinicalTrials.gov Identifier: NCT03226522).  
5.3. 
STUDY PURPOSE/RATIONALE 
1.  Experience with similar supportive care therapies (in terms of efficacy and tolerability): This is the first time that 
AXS-05 has been studied in humans for the purpose of decreasing smoking. Other smoking cessation treatments 
have, however, made a dramatic impact on smoking. Abstinence rates for unassisted quit attempts are less than 5%4, 
and new approaches to successful treatment of our current population of smokers are urgently needed.  
Pharmacotherapy is the primary treatment used by people who smoke to quit smoking, with 29.9% of smokers 
attempting to quit smoking with the use of a medication3. Currently, there are seven FDA approved smoking 
cessation medications including varenicline, bupropion, nicotine patch, gum, lozenge, inhaler, and nasal spray4. 
Approved medications vs. placebo roughly double the chances of quitting during any given quit attempt; efficacy vs. 
placebo of RR=1.7 (nicotine gum) to RR=2.4 (varenicline)5.  Most of the medications used for smoking are moderately 
well tolerated.  One study comparing varenicline vs. placebo found the following incidence rates: nausea (28.1% vs. 
8.4%), headache (15.5% vs. 12.2%), vivid dreams (10.3% versus 5.5%)22. A meta-analysis23 (N > 177,000) on side 
effects from nicotine replacement (the most commonly used smoking cessation medications) showed the following 
rates vs. placebo (all p < 0.001): Headache (9.7% vs. 4.7), nausea (8.5% vs. 5.1%), insomnia (11.4% vs. 8.0%), skin 
irritation – patch (19.5% vs. 6.9%), mouth soreness – gum/lozenge (5.4% vs. 2.9%)23. A study on (N=225)24 nicotine 
patch adherence (daily use for 28 days), found that 64.7% of participants were non-adherent and stopped regular use 
(30% forgot to use it, 15% had side effects, 10% relapsed, 7% financial challenges). A study (N=662) on nicotine gum 
adherence (used of 75% of prescribed gum) showed that 73.4% were non-adherent, most frequently due to 
forgetting to use the gum25. A study on bupropion adherence (twice daily use x 6 weeks) showed non-adherence of 
only 37%61. Thus, most of the FDA approved smoking cessation medications, except perhaps bupropion, have 
significant associated side effects and problems with adherence for various reasons. Development of an orally 
administered medication (like bupropion) with a low incidence of side effects has the potential for comparatively 
high-level adherence and subsequently higher associated smoking abstinence rates.  
2.  Description of how the study therapy is different from current treatment paradigms, and how this difference 
might help meet an unmet supportive care need:  The novel use of DXM for smoking cessation promises the 
potential approval of a new class of drugs in addition to current options for smoking cessation. The addition of 


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19 
bupropion makes this drug safer and more effective by increasing CSF concentrations of DXM while decreasing total 
dose. Usefulness of this drug in smokers would potentially open the door to further exploration of drugs with effects 
on sigma-1, NMDA, or α3β4 nAChR.   
3. What the potential benefits are for this supportive care intervention:  This study is designed to produce evidence 
that AXS-05 (primarily DXM) is significantly more effective than bupropion alone at inducing a spontaneous reduction 
in smoking. Additionally, an assessment of mechanism is provided to estimate the impacts of known physiologic 
activities. Each of these inquiries is designed to guide future study in a fully powered trial through the Strategic 
Alliance funding mechanism. The study is promising because DXM has shown to reduce nicotine self-administration 
in animals and AXS-05 has a reasonable side effect profile in humans. The study also has a high potential for impact 
because AXS-05 could easily be made available to thousands of smokers due to an existing pharmaceutical 
infrastructure with large scale production and national distribution.  
 
 
 


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6. OBJECTIVES AND ENDPOINTS 
 
 
Objective 
Endpoint 
Analysis 
Primary (1)  
 
To evaluate the impact of AXS-05 
compared to BUP on change in smoking 
intensity from baseline to the 3-Week 
Follow-Up Visit. 
Number of cigarettes smoked per day will be 
assessed at baseline through smoking diary and 
at the 3-week Follow-up visit by smoking diary. 
Breath Carbon Monoxide testing will also be 
performed as well as saliva cotinine testing. 
See 
Section 
13.4 
Key Secondary (2)  
To compare AXS-05 to BUP on 7-day 
abstinence test between the 3 Week 
Follow-up and 4 Week Follow-up study 
visits. 
7 day abstinence test starting at midnight of the 
3 Week Study Visit and ending at the 4 Week 
Study Visit through self-reported smoking 
abstinence with biochemical confirmation using 
CO breath testing and salivary cotinine. 
See 
Section 
13.5 
Key Secondary (3)  
To assess potential baseline variables for 
an association with smoking behavior 
outcomes listed in objectives. 
Potential predictors include age, gender, race, 
education, baseline nicotine dependence, 
stress, anxiety, depression, and self-efficacy.  
See 
Section 
13.5 
Key Secondary (4)  
To compare AXS-05 to BUP on adherence 
to self-administered drug. 
Adherence to self-administered drug will be 
measured 
via 
Medication 
Use 
Diaries 
completed by participants throughout the study 
and reviewed weekly at Study Visits.   
See 
Section 
13.5 
Key Secondary (5)  
To compare AXS-05 to BUP on tolerability 
through weekly, open-ended survey to 
assess potential side effects.  
 
Tolerability of administered medications will be 
measured via weekly, open-ended surveys that 
collect information regarding potential side 
effects. 
See 
Section 
13.5 
Key Secondary (6)  
To compare AXS-05 to BUP on incidence 
of adverse events.  
The incidence of adverse events or serious 
adverse events will be assessed utilizing FDA 
accepted 
reporting 
guidelines 
on 
these 
outcomes.   
See 
Section 
13.5 
Key Secondary (7)  
To measure urine drug levels of DXM at 
weeks 
1-4 
and 
assess 
potential 
correlation of these levels with smoking 
behavior and side effects. 
Urine drug levels of dextromethorphan will be 
measured at baseline and all four time points 
with correlation assessed between urine DXM 
at each time point and smoking behavior across 
all study participants and across individual 
cohorts.  
See 
Section 
13.5 
Key Secondary (8)  
To compare AXS-05 to BUP on changes 
from baseline vs. weeks 1-4 Follow-up 
visits on the following: smoking urges, 
withdrawal symptoms, smoking reward, 
stress, anxiety, depression, self-efficacy, 
sleep disturbance, agitation, and emotion 
regulation. 
Changes in smoking urges and withdrawal 
symptoms, stress, anxiety, depression, sleep 
quality and self-efficacy will be assessed by self-
report at baseline vs. all four Follow-up Visit 
time points.  
See 
Section 
13.5 
Key Secondary (9)  
To compare AXS-05 to BUP on change 
from baseline to weeks 1-4 on daily 
assessment of the following: urge 
frequency, urge severity, and irritability.  
Smoking urges and mood irritability will be 
assessed via daily entries in diary reports.  
See 
Section 
13.5 


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7. INVESTIGATIONAL PLAN 
7.1. 
STUDY DESIGN 
1.  Specifics about study type:  The proposed study is a double-blind, randomized active -controlled 4-week trial of 
60 daily smokers attempting to quit. Up to 150 individuals will be consented with up to 70 individuals being 
randomized. The main goal is to have 60 randomized smokers’ complete assessments at study visit 4. Smokers will be 
randomized with 1:1 allocation to AXS-05 (45 mg Immediate Release DXM + 105 mg Sustained Release BUP) vs. 105 
mg Sustained Release BUP. Medications will be dosed twice daily (1 tablet for first 3 days) and continued for four 
weeks in each group with laboratory testing at baseline and then once per week to assess the number of cigarettes 
smoked per day with objective confirmation through assessment of expired breath carbon monoxide (CO) and 
salivary cotinine. Additional testing on smoking behavior will include abstinence testing during a 7-day abstinence 
test (starting at midnight after the 3-Week Follow-up Study Visit and ending at the 4-Week Follow-up Study Visit). 
Potential drug side effects will be assessed through repeated survey administration and spontaneous report. 
Adherence to drug use will be assessed through Medication Use diaries. Urine drug levels will be collected at Week 1-
4 Follow up Visits to allow for correlation of urine drug levels to the number of cigarettes smoked per day (Cotinine, 
CO) and side effects. Because DXM and BUP have independently been shown to impact smoking urges, withdrawal, 
stress, depression, and anxiety, changes in these psychiatric variables will be assessed throughout the trial and 
evaluated as potential mediators of effect on smoking behavior.   
2.  Design and supporting rationale:  
 
 
Selection of Subjects 
Recruitment: Subjects will be recruited through the Duke Center for Smoking Cessation (CSC) using standard 
recruitment procedures including television, radio, web-based (ex: Facebook, Instagram, Craigslist, JobFinder, 
StudyKik, etc.), print-based media (ex: JobFinder, etc.), and flyers. All ads will feature a phone number and contact 
email for potential participants and can be found in the Recruitment section on eIRB. This study will also recruit 
participants through the Duke Primary Care Research Consortium (PCRC). Patients will be contacted through the Duke 
PCRC and scheduled for appointments with study personnel at the CSC. Authorization has been provided by the DPC 
Research Consortium, which will provide access to smokers who have consented to be contacted for research. The 
Research Consortium manages multiple studies to avoid conflict between studies and will provide access to a few DPC 
Clinics. DPC includes a network of 40 primary care clinics throughout Duke University Health System. Patients who 
attend visits with DPC medical providers at within Duke Primary Care are screened to see if they are willing to be 
contacted to find out about available research. DPC patients who are identified within the Electronic Health Record as 
being “current smokers” will be available for contact for our study. Using a regularly generated report, research staff 
will mail these patients letters from their medical providers that describe the study. The letter will also include a phone 
number if the patient does not want to be contacted about the study. Research staff will call the patients that do not 
opt-out and describe the study. If they are interested and meet inclusion criteria, the research staff will schedule them 
for a screening visit at the Duke Center for Smoking Cessation (CSC) (central study site). In addition, participants will 
be recruited using IRB-approved flyers placed around the Triangle Area (Durham, Raleigh and Chapel Hill). Examples of 
locations where flyers may be placed include: grocery stores, churches, retail stores (ex: Walmart, Target, etc.), 
restaurants, banks, bus stops and gas stations. In addition, this study will recruit participants through the Digital Signage 
program occurring throughout DUH, Duke South Clinics, Duke Medicine Pavilion, Duke Cancer Center and other clinical 
facilities at Duke University Hospital. Digital signage will also be used in other locations throughout the Triangle Area 
(Durham, Raleigh and Chapel Hill). Futhermore, potential subjects will be recruited through pre-screen failures from 
other studies at the CSC. There are currently several studies recruiting smokers from communities in and around 
Durham, North Carolina through newspaper flyers, internet and TV advertisements, and word-of-mouth. If potential 
subjects fail to meet the pre-screening study requirements for these studies (Pro00072077, Pro00089760, 
Pro00042277) at the CSC, but are still interested in research, they will be routed to a CTA to be pre-screened for this 
study over the phone. If potential subjects meet the pre-screening study requirements and are still interested in 
participation, they will attend a physical screening session at the Duke CSC, located at 2424 Erwin Road, Suite 201, 
Durham, NC  27705. At the screening on-site visit, a CTA will meet with the patient in a private area of the CSC (consent 


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room) and provide the patient with the Study Consent Form for review. Finally, web-based recruitment methods will 
use a REDCap Survey that includes both the phone script as well as the screening questions. This survey will allow 
participants to complete the phone consent process immediately. Incoming survey responses will be reviewed by a 
Technician at the Duke Center for Smoking Cessation (CSC). Potential participants who pass the phone consent will be 
called after review to schedule a screening visit. Potential participants may also be called if survey responses require 
additional review or clarification. Survey responders who do not qualify for the study will not be called.  
CSC subject recruitment in the past has shown demographic distribution outlined in Table 2. We will recruit smokers 
into this study who state that they are willing to attempt to quit smoking for at least 7 days. Evaluation of this 
population should allow for an unencumbered assessment of pharmacological effects of the drug on smoking behavior. 
Table 2: Duke Center for Smoking Cessation Recruitment Population 
Female 
51.1% 
Mean Age 
46.3 
White 
49.2% 
Black 
44.9% 
Educ. > high school  
48.4%  
Mental Illness  
30.5%  
Planned number of subjects: A total of approximately 120 subjects will be consented with 66 subjects being 
randomized and enrolled with the goal of having 60 randomized subjects (30 per arm) complete assessments through 
study visit 4.  With expected attrition of 10% between enrollment and study completion, we expect to enroll 
approximately 66 participants to obtain 60 completers (completer is defined as having completed assessments 
through study visit 4).  
Randomization: Subjects will be randomized with stratification by Fagerstrom Test for Nicotine Dependence score 
(assessment of nicotine dependence) and gender to ensure roughly equal distribution of these characteristics 
between the two groups.   
Phone Screening, Screening Visit, and Informed Consent: People who smoke who call in to the CSC will be screened 
by phone by a Clinical Research Specialist. If they pass phone-screening criteria, they will be scheduled for a 
Screening Visit at the Duke Center for Smoking Cessation. At the Screening Visit, after obtaining informed consent 
and signing the Study Consent Form, they will complete several screening questionnaires (PHQ-9, GAD-7. FTND, 
MMS, MDQ, SCOFF), medical history and personal information forms, a physical exam, CO breath testing, EKG, blood 
test, urine drug screen, and urine pregnancy test (if applicable). If they pass criteria at the Screening Visit, they will be 
scheduled for the Baseline Assessment Visit. Patient will be assigned a unique screening number and a screening log 
will be maintained. 
Baseline Assessment Visit: At the Baseline Assessment Visit, participants will perform CO breath testing, urine 
pregnancy test (if applicable), and a detailed review of systems. If cleared they will be enrolled in the study (assigned 
a Study ID enrollment number) and randomized to either AXS-05 (study group) or Bupropion (control group).  
Participants will then receive the Baseline Questionnaires (see below) as well as Baseline expired CO and urinary 
cotinine testing.3.  Drug Dose: Subjects will be randomized with 1:1 allocation to AXS-05 (45 mg Immediate Release 
DXM + 105 mg Sustained Release BUP) vs. 105 mg Sustained Release BUP. Medications will be provided to 
participants at the Baseline Study Visit and continued for four weeks in each group.   
Appointment Reminders: Participants will be provided with the option to receive text message appointment 
reminders. This is discussed at two different time points. At the Phone Screen, participants provide verbal consent via 
phone. If they pass the phone screen and are scheduled for their Screening Visit, participants are asked if they would 


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like to receive an appointment reminder via text. If the participant “opts in”, then they are asked to confirm their 
phone number and cell phone provider. They will then be sent up to two different text message appointment 
reminders—three days prior and one day prior. Each message will ask them to reply to confirm their appointment. If 
they confirm, no more text messages are sent. If they are unable to attend, they are asked to call the Center for 
Smoking Cessation line to reschedule. Once the participant attends their Screening Visit, they are asked to sign the 
Adult Consent form, which will again ask if they would like to receive text message appointment reminders (in the 
same fashion as discussed above). Participants can opt out at any time but must verbally convey this request to 
research staff or submit it in writing. All standard messaging rates will apply to the participant. Messages will 
originate via Microsoft outlook, which has been approved by Duke University Health System Information Security. 
Participants will be informed that because text messaging does not provide a completely secure and confidential 
means of communication, please do not text message if you wish to communicate in private.  
Study Group Dosing:  Dextromethorphan Immediate Release 45mg + Bupropion Sustained Release 105 mg  
Provided by Axsome as a single tablet containing both drugs  
Dose Timing: For the first three days, take one tablet in the morning on an empty stomach (one hour prior to the 
morning meal or two hours after the morning meal). Thereafter take one tablet two times per day, on an empty 
stomach, at least 8 hours apart and 1 hour prior to a meal, or 2 hours after a meal. 
Control Group: Bupropion Sustained Release 105 mg 
Provided by Axsome as a single tablet 
Dose Timing: For the first three days, take one tablet in the morning on an empty stomach (one hour prior to the 
morning meal or two hours after the morning meal). Thereafter take one tablet two times per day, on an empty 
stomach, at least 8 hours apart and 1 hour prior to a meal, or 2 hours after a meal. 
Packaging of Medications:  Bupropion provided to controls will be administered in such a way as to match study 
group medication appearance and schedule. The Clinical Trial Materials Manager will package all medications such 
that AXS-05 and Bupropion are packaged identically and research assistants interacting with patients are unaware of 
which drug is given.   
4.  Eligible subject population  
For Inclusion and Exclusion Criteria please see this list on pages 9 and 10.  
Use of Inclusion/Exclusion Criteria: The primary considerations for the use of inclusion/exclusion criteria include 
consent (English, age), patient safety (illness, medications, blood tests, pregnancy), and generalizability (willingness 
to quit, cigarette use, drug and alcohol use, psychiatric illness).  
5.  Number of subjects: Sample size will be N= 60 with pre-established randomization of numbers from 1-60 such 
that 30 are allocated to study group and 30 are allocated to controls. Participants who drop out and do not complete 
assessment through 3-week follow-up visit (Visit 4) will be replaced to reach a total of 60 study randomized  
completers and based on a 10% drop-out rate between enrollment and study completion, we are expecting to enroll 
approximately 70 subjects after having consented up to 150.  
6.  Number of centers:  The study will be conducted at Duke Center for Smoking cessation (one site).   
7.  Treatment duration:  The study treatment and assessment duration is provided in the table below. The study 
contains a Screening Visit followed by a Baseline Visit and four follow-up visits (Table 3 below). 
8. Study Assessments:  Study assessments are outlined in Table 3 and details are provided in full within the 
Appendices. All study visits (Visits 2, 3, 4, and 5) should be completed within +/- 5 days of the visit.  


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Table 3: Assessments and Assessment Visits 
Assessments and Assessment Visits  
Screen Visit 
Baseline 
1-week  
follow-up  
visit 
2-week  
follow-
up  visit 
3-week  
follow-
up visit 
4-
week  
follow-
up  
visit 
6 
week 
Phone 
Call 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Phone 
Call 
 
Screening 
 
1 
Screening Visit Checklist 
(Inclusion/Exclusion Criteria) (items 
above)  
X 
X* 
 
 
 
 
 
2. 
Patient Health Questionnaire (PHQ-9) 
Depression62 
X 
 
 
 
 
 
 
3. 
Generalized Anxiety Diagnosis (GAD-
7)63  
X 
 
 
 
 
 
 
4.  
Fagerstrom Test for Nicotine 
Dependence (FTND) (6 items)64 
X 
 
 
 
 
 
 
5. 
Modified Mini Screen (MMS) 
X 
 
 
 
 
 
 
6. 
Mood Disorder Questionnaire (MDQ) 
X 
 
 
 
 
 
 
7. 
SCOFF Questionnaire 
X 
 
 
 
 
 
 
8. 
Demographics Questionnaire 
X 
 
 
 
 
 
 
9. 
Contact Information 
X 
 
 
 
 
 
 
10. 
Medical History + Medications  
X 
 
 
 
 
 
 
11. 
Smoking History (non-standardized) 
(10 items) 
X 
 
 
 
 
 
 
12.  
Review of Systems (ROS) 
X 
 
 
 
 
 
 
13. 
Physical Exam  
X 
 
 
 
 
 
 
14. 
EKG 
X 
 
 
 
 
 
 
15. 
CBC, CMP, HgbA1C  
X 
 
 
 
 
 
 
16. 
Urine Drug Screen (5 item)15  
X 
 
 
 
 
 
 
17. 
Urine Pregnancy Test14 
X 
X 
 
 
 
 
 
18. 
Screening Week Smoking Diary 
X 
 
 
 
 
 
 
*An abbreviated evaluation of inclusion/exclusion criteria will be assessed at the baseline visit to provide the most up to 
date data prior to enrollment, including a urine pregnancy test. 
 
 


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AIM1: Smoking Abstinence  
 
1. 
Carbon Monoxide Breath Test65 
X 
X 
X 
X 
X 
X 
 
2. 
Salivary Cotinine66   
 
X 
X 
X 
X 
X 
 
3. 
Recent Smoking Questionnaire (non-
standardized) (4 items)  
 
X 
X 
X 
X 
X 
X 
4. 
7-Day Smoking Abstinence Test 
 
 
 
 
X 
X 
 
5. 
6 week Phone Call Smoking Status 
Questions (2 Items) 
 
 
 
 
 
 
X 
 
AIM 2: Adherence and Tolerability 
 
1. 
Smoking Diary  
 
 
X 
X 
X 
X 
 
2. 
Urge and Irritability Diary  
 
 
X 
X 
X 
X 
 
3. 
Medication Use Diary   
 
 
X 
X 
X 
X 
 
4.  
Medication Side Effects Log67  
 
 
X 
X 
X 
X 
 
5. 
End of Treatment Side Effects 
Questionnaire 
 
 
 
 
 
 
X 
6. 
Urine testing for AXS-05 (DXM/BUP)  
 
 
X 
X 
X 
X 
 
7. 
PHQ-9 question 9 + C-SSRS 
(suicidality assessment)* 
 
X 
X 
X 
X 
X 
X 
8.  
 Modified Mini Screen (MMS) 
Section C + BPRS (psychosis 
assessment)* 
 
X 
X 
X 
X 
X 
X 
 
 
AIM 3: Mechanism (nicotinic, affective and cue-based learning)  
 
1.  
Mood and Physical Symptoms Scale 
(MPSS-2)68  
 
X 
X 
X 
X 
X 
 
2.  
Minnesota Nicotine Withdrawal 
Symptoms Scale (MNWS)69  
 
X 
X 
X 
X 
X 
 
4. 
State-Trait Anxiety Inventory (STAI) 
(40 items)70 
 
X 
X 
X 
X 
X 
 
5. 
Center for Epidemiologic Studies 
Depression Scale-Revised (CESD-R) 
(20 items)71  
 
X 
X 
X 
X 
X 
 
6.  
Modified Cigarette Evaluation 
Questionnaire (mCEQ) (12 items) 
 
X 
X 
X 
X 
X 
 
7.  
Pittsburg Sleep Quality Index (PSQI) 
(10 items)  
 
X 
X 
X 
X 
X 
 


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* If an enrolled participant scores greater than 0 on PHQ-9 question 9 (suicidality) they will complete the Columbia- 
Suicide Severity Rating Scale (C-SSRS) with a clinician. If the participant answers “Yes” to any item on the MMS, they 
will complete the Brief Psychiatric Rating Scale (BPRS) with a clinician.  
Special Tests  
7 Day Abstinence Test: At the Visit 4, subjects are asked not to smoke at all for the next 7 days. They will be paid an 
additional $70 to be abstinent6. Smoking abstinence will be tested in the 7 day abstinence test using self-reported 
total abstinence during the period with biochemical confirmation via expired carbon monoxide (CO) breath test < 
7ppm (96.0% sensitivity and 93.3% specificity)72 and salivary cotinine with a cutoff of < 13 ng/ml to define abstinence 
(sensitivity, 86.5%; specificity, 95.9%)73.  
Participant Compensation: Participants will receive the following compensation for attending visits and completion 
of various aspects of the study.   
Screening Visit = $0 
Baseline Visit (Visit 1) = $20  
1 Week Follow-up Visit (Visit 2) = $30  
2 Week Follow-up Visit (Visit 3) = $40 
3 Week Follow-up Visit (Visit 4) = $50 
4 Week Follow-up Visit (Visit 5) = $50  
Smoking/Urges and Irritability Diaries = $120 ($30 per visit x 4 visits)   
7 Day Abstinence Test = $70 (during week 4 visit only)  
6 week Follow-Up Call= $0 
With payments for various parts of completion the maximum possible a subject can obtain is the following:  
Baseline Visit (Visit 1) = $20  
1 Week Follow-up Visit (Visit 2) = $30 + $30 (diary) = $60  
2 Week Follow-up Visit (Visit 3) = $40 + $30 (diary) = $70 
3 Week Follow-up Visit (Visit 4) = $50 + $30 (diary) = $80 
4 Week Follow-up Visit (Visit 5) = $50 + $30 (diary) + $70 (7-Day Abstinence Test) = $150 
Total = $380  
Use of ClinCards for compensation:  Participants will be compensated using ClinCards to decrease attrition in the 
study. ClinCards are preloaded debit cards, on which credit can be added by study staff. This decreases the length of 
time until participants are compensated by several weeks and prevents participants from having to pay a check 
cashing fee. The Study Coordinator or Clinical Research Specialist will provide each participant with a ClinCard at the 
Baseline Visit and will add the compensation to the card. After approval by Travel & Reimbursement, the participant 
will have the money loaded onto the card.  
8. 
Brief Agitation Measure (3 items)  
 
X 
X 
X 
X 
X 
 
9. 
Perceived Stress Scale (PSS-4) (4 
items) 
 
X 
X 
X 
X 
X 
 


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7.1.1. 
DOSE MODIFICATION 
If side effects from either of these drugs are observed and determined to be minor, the medication dosing in either 
group may be changed with the evening dose either moved earlier in the day or eliminated.   
7.1.2. 
SAFETY CONSIDERATIONS 
We plan to ask participants about the specific side effects which have been noted previously on AXS-05 at 105 mg 
BUP and 45 mg DXM (list provided in the Appendix 10). If participants are found to have any of these symptoms they 
will be assessed by the study physician or study medical provider to determine its severity, whether it may have been 
caused by the drug, and whether it requires dose adjustment or discontinuation of the drug.    
7.1.3. 
MISSED DOSES 
Missed doses of medications will not be replaced. There will be no “catch up” for missed doses. We will capture data 
on missed doses through the medication adherence diary.   
7.1.4. 
CONCOMITANT MEDICATIONS/THERAPIES 
A medication list is provided for medications which are contraindicated in the study (see Appendix 1). Participants 
will be asked to report the use of any new medications during the study, including medications containing 
Dextromethorphan. If new medications are started, the study physician or study medical provider will assess whether 
or not the participant must be removed from the study.   
7.1.5. 
STUDY DRUG BLINDING 
The study is double blinded such that participants, research assistants, and the study physician (each of whom have 
contact with participants) are unaware of group allocations. Pill bottles provided to participants will feature generic 
research labels (Medication X vs. Medication Z) through the Clinical Trial Materials (CTM) manager at the Duke 
Center for Smoking Cessation. The Clinical Research Coordinator (CRC), who oversees operations and has no contact 
with participants, will be aware of participant group allocation. Emergency un-blinding procedures are described in 
11.3   
7.1.6. 
RANDOMIZATION 
Prior to the study start date, a stratified (gender and FTND score) randomization list will be generated through the 
REDCap Randomization Module74 for a sample of 60 with 1:1 allocation to study and control groups via random 
permutation of integers without replacement75. The randomization list will be accessed sequentially as each 
participant is enrolled. Patients not completing three weeks of assessments (Visit 4) in this study will be replaced to 
previous randomized treatment group and will not be randomized.  
7.2. 
RATIONALE FOR SELECTION OF DOSE, REGIMEN, AND TREATMENT DURATION 
 A dosing regimen of DXM IR 45 mg combined with BUP SR 105 mg, twice-a-day, is utilized in this study because of 
the following: 1) it is believed that sufficient and sustained levels of DXM in the CNS will be obtained and 2) there is 
preliminary evidence that the proposed dose of AXS-05 for 28 days will be safe based on the three completed Phase 
1 studies and two ongoing Phase 2/3 studies in TRD and agitation in AD. 
7.3. 
RATIONALE FOR CORRELATIVE STUDIES 
No correlative study will be performed.  
7.4. 
DEFINITION OF EVALUABLE SUBJECTS, ON STUDY, AND END OF STUDY 
This study defines a subject as evaluable if they have completed 4 of the 5 study visits.   
7.5. 
EARLY STUDY TERMINATION 
This study can be terminated at any time for any reason by the PI-sponsor. If this occurs, all subjects on study should 
be notified as soon as possible. Additional procedures and/or follow up should occur in accordance with Section 10.6, 
which describes the procedure for prematurely withdrawn patients.  


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8. STUDY DRUG 
8.1. 
NAMES, CLASSIFICATION, AND MECHANISM OF ACTION 
AXS-05 (AXS-05) (STUDY DRUG)  
Information on drug structure, formulation, and manufacturing may be found within the Investigators Brochure 
Version 4.0 [IND 129633] Section 3: Chemistry and Pharmaceutical Information included in this application. 
BUPROPION SR 105 mg (CONTROL DRUG)  
Information on drug structure, formulation, and manufacturing may be found within the Investigators Brochure 
Version 4.0 [IND 129633] Section 3: Chemistry and Pharmaceutical Information included in this application.  
8.2. 
  PACKAGING AND LABELING 
Blinded study drug(s) will be provided in bottles to the CTM by Axsome. Axsome will ship AXS-05 and bupropion 
tablets in bottles identical to packaging used in prior studies. Bottles will be stored at Duke. Labels comprising the 
following information will be applied to each bottle:  subject number, visit number, current year, “Duke Center for 
Smoking Cessation”, IRB Protocol number, brief description of pack contents (with neutral language accounting for 
the blind/active-control), Center front desk phone number, and “For investigational use only” tag. 
8.3. 
  SUPPLY, RECEIPT, AND STORAGE 
The Clinical Trial Materials (CTM) manager at the Duke Center for Smoking Cessation will be responsible for receiving, 
storing, and inventorying the study drug(s). All study drug(s) will be kept in a locked cabinet with thermometer inside, 
which will be checked weekly and recorded in a study temperature log. Active medications will be kept on separate 
shelves. The key to open the cabinet containing the study drug(s) will be kept in a separate drawer, which itself is 
locked by a second key which will be stored inside a key box in a hallway externally adjacent to the room containing 
the study drug(s).  
8.4. 
  DISPENSING AND PREPARATION 
Study medication provided by Axsome (Section 8.2) will be dispensed by the CTM.  Study technician(s) will “order” 
medications from the CTM Manager by sending an email when supplies for each respective medication group are 
running low. The CTM Manager and a deputized un-blinded second individual will conduct preparation of the study 
drug(s) according to both the order sent by study technician. Each order will consist of the preparation of anywhere 
from 12-16 new bottles. The CTM Manager and the second individual will review the prepared bottles to ensure that 
the full “order” has been met and then dispense the bottles to study technician(s) in advance of the relevant study 
visit(s). Details of the distribution of the bottles will be contained in a separate un-blinded study drug distribution 
sheet as well as within the blinded study medication dispensing log. 
8.5. 
  COMPLIANCE AND ACCOUNTABILITY 
The CTM Manager will maintain an un-blinded inventory log only accessible to study team members who are not 
blinded, which will record date and amount dispensed of study drug(s) for every study visit, as well as the study and 
visit number. The log will contain a section that “counts” up and down the total inventory of each study drug as items 
are added and subtracted.  Separately, a blinded inventory log will be co-maintained by the CTM Manager and study 
technician, which will detail for every study visit the: date/time ordered, date prepared, initials of individuals who 
conducted preparation, subject number, visit number, days of medication included, date received by study 
technician, initials of study technician who received study drugs, date dispensed to subject, date study drug(s) 
returned to the CTM Manager and the initials  of study technician who returned study drugs to CTM Manager. 
8.6. 
  DISPOSAL AND DESTRUCTION 
The CTM Manager will dispose of unused study drug(s) by placing into bins, which are collected by Stericycle (waste 
services) by contract for ultimate destruction. 


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9. ELIGIBILITY 
For Inclusion and Exclusion Criteria please see this list on pages 9 and 10.  
Use of Inclusion/Exclusion Criteria: The primary considerations for the use of inclusion/exclusion criteria include 
consent (English, age), patient safety (illness, medications, blood tests, pregnancy), and generalizability (willingness 
to quit, cigarette use, drug and alcohol use, psychiatric illness).  
 


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10. TRIAL PROCEDURES AND ASSESSMENTS 
Overview of Assessments: Medications will be continued for four weeks in each group with laboratory testing at 
baseline and then once per week to assess the number of cigarettes smoked per day with objective confirmation via 
expired breath carbon monoxide (CO) and salivary cotinine at each visit. Additional testing on smoking behavior will 
include abstinence testing during a 1 week “practice quit” abstinence test (performed starting midnight after the 3 
Week Follow-up visit). Potential drug side effects will be assessed through repeated survey administration and 
spontaneous report. Adherence to drug use will be assessed through Medication Use Diaries. Urine drug levels will be 
collected at Visits 2-5 to allow for correlation of urine drug levels to the number of cigarettes smoked per day 
(Cotinine, CO) and side effects. Because combination DXM and BUP have independently been shown to impact 
smoking urges, withdrawal, stress, depression, and anxiety, changes in these psychiatric variables will be assessed 
throughout the trial and evaluated as potential mediators of effect on smoking behavior. All study visits (Visits 2, 3, 4, 
and 5) should be completed within +/- 5 days of the scheduled visit.  
Study assessments are outlined in Table 3 and details are provided in full within Appendix 3-16. 
Special Tests  
7-Day Smoking Abstinence Test: Starting at midnight after the 3 Week Follow-up Visit, subjects will be asked not to 
smoke at all for the following 7 days, and will be paid an additional $70 to be abstinent. Smoking abstinence will be 
tested in the 7 Day Abstinence Test using self-reported total abstinence during the period with biochemical 
confirmation via expired air carbon monoxide (CO) breath test < 7ppm (96.0% sensitivity and 93.3% specificity)72 and 
salivary cotinine with a cutoff of < 13 ng/ml to define abstinence (sensitivity, 86.5%; specificity, 95.9%)73.  
10.1. SCREENING EXAMINATION 
The screening examination will take place during the screening visit. Informed Consent will be signed by the 
participant before the physical exam and blood testing is performed. Subject data to be collected at the Screening 
Visit includes demographic information, contact information, medical history, smoking history, review of systems 
(ROS), as well as assessments for depression (PHQ-9), anxiety (GAD-7), nicotine dependence (FTND), psychotic and 
mood disorders (MMS and MDQ) and eating disorders (SCOFF). In addition, a physical exam, EKG, blood testing for 
CBC, CMP, A1C level, saliva testing for cotinine, urine drug screen, and urine pregnancy test will be done.   
Phone Screening Procedures 
The CRS will conduct phone screens to verify that potential subjects fit the basic inclusion criteria for this particular 
study. The CRS will be familiar with the IRB-approved study protocol, informed consent form, and phone script for 
the study. The CRS will be responsible for scheduling physical screens, documenting on the phone screen forms, and 
providing directions and appointment reminders for those callers that fit the inclusion criteria. Each potential subject 
will be given a brief description of the study to assess eligibility and interest. An IRB-approved phone script will be 
followed while conducting the phone screen. During the phone screen, the CRS will use the AUDIT-C (Appendix 28) as 
one way to verify if potential subjects fit the basic inclusion criteria. In addition, the CRS will ask potential subjects if 
they are willing to be smoke-free for 7 days. Each potential subject will be called up to three times and/or have three 
detailed messages left. If a subject is not contacted and a message is not left after two calls he/she will not be 
considered further for participation in the study. If the CRS leaves three messages for the potential subject and that 
subject does not call back, then no further attempts at contact will be made until the potential subject re-establishes 
contact. Participants will also be asked if they would like to receive text message reminders. If they opt in, phone 
number and cell phone carrier will be recorded. Participants will be informed that standard messaging rates will 
apply and be their responsibility. They can choose to opt out at any time. Two appointment reminders will be sent 
three days prior and one day prior and they will be asked to reply to confirm their appointment.  
Once a subject has successfully completed the phone screening process and is eligible for a physical screening, the 
CRS will then schedule the appointment during the study Physician/Physician Assistant’s specific work hours. The 


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physical screening appointments will be entered on the Outlook calendar; changes to appointments, such as 
cancellations and rescheduled visits should be documented on the calendar. It will be the responsibility of the CRS to 
check the calendar on a regular basis to ensure proper scheduling and preparation for these visits. The CRS should 
mail or e-mail an appointment notification letter and driving directions to the potential subject as soon as possible 
after completing the phone screen. If the subject does not want to provide a mailing address or e-mail address, then 
the CRS will be responsible for giving driving directions and instructions via telephone. The Preliminary Contact Form 
or a report containing the potential subject’s preliminary phone contact data (if the phone screen is conducted using 
Access) will be completed by the CRS in anticipation of the Screening Visit. 
Screening Visit Procedures 
After granting their informed consent, potential subjects will be given the HIPAA Notice of Privacy Practices and sign 
an Acknowledgement of Receipt Form. They will also complete a demographics form (Appendix 25), contact 
information form (Appendix 26), medical history form and smoking history form. In addition, they will complete the 
ROS, PHQ-9, GAD-7, FTND, MMS, MDQ and SCOFF Questionnaire, and will have their blood pressure, pulse, weight, 
height, temperature, and expired air CO measured. Subjects will provide blood (maximum of 20mL for tests to 
measure general health), and urine for urinalysis and illicit drug testing. Women of childbearing potential will also 
have a urine pregnancy test. The study physician or PA will perform a physical examination and an EKG. The 
screening visit will last approximately two hours. They will be asked to complete a Cigarette Use Diary with the 
number of cigarettes they smoke from the day of the screening visit to Visit 1.  
Blood and urine specimens will be sent to LabCorp for processing. The results of laboratory blood and urine tests will 
not routinely be given to participants to send or be sent to their physician to include in their medical record; 
however, if the subject’s lab results are outside the acceptable range for participation in the study, the Physician/PA 
will send the subject a medical exclusion letter and a copy of the lab results. Participants who are accepted in the 
study but need medical follow-up due to minor abnormalities in lab results will also be informed by letter from the 
Physician/PA. A copy of the laboratory results will be included with the letter, which will also indicate that the 
condition does not interfere with his/her participation in the study. If the participant does not appear for the 
Screening Visit within 30 days of the screening phone call, the Preliminary Contact Form will be shredded. 
10.2. TREATMENT PERIOD 
Visit 1 
The first study visit (also referred to as Baseline Visit) will take place approximately 1 week after the Screening Visit 
but no longer than 30 days after the Screening Visit. Subjects will provide a urine pregnancy test (if they are of child 
bearing potential) to provide greater assurance that this eligibility criteria has not changed. Subjects will complete 
baseline questionnaires and tests and will be randomized to AXS-05 or Bupropion. Baseline questionnaires include: 
Recent Smoking Questionnaire, MPSS-2, MNWS, PSS-4, STAI, CES-D, PSQI and mCEQ. Participants will also complete 
expired CO and salivary cotinine testing and have their blood pressure, heart rate and weight measured. 
Subjects will initially be given a 12-day supply of study medications. This includes 7-days of medications to last until 
the next study visit (all study visits are 1 week apart) and an additional 5 days of medications to allow for the 
possibility of a missed visit and the need to reschedule within 5 days of the missed visit. Participants will receive 
verbal and written instructions on how to take them. At follow up visits, participants will be given enough 
medications so that their total supply allows for 1 week + 5 days in case of a missed visit.  At the Week-3 Follow Up 
Visit (Visit 4), participants will be provided enough medication to continue to the final day of medication use. 
(Subjects will be called within three days after the first day of treatment to make sure the medications are being used 
as directed). 
Subjects will also be given diaries to record medication use, irritability, urges, and the number of cigarettes smoked 
each day and will be instructed to return the diaries at the next visit. They will also be asked to return any unused 


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medications for proper disposal and compliance monitoring. Subjects will also complete a Medications Side Effects 
Log and discuss any side effects with Physician or PA at the next visit. 
Visit 2 (1-Week Follow-up Visit) 
The second visit (also referred to as 1 Week Follow-up visit) will take place approximately 1 week after Visit 1. 
Subjects will complete repeated questionnaires and tests. Repeated questionnaires include: Recent Smoking 
Questionnaire, PHQ-9 Question 9 and C-SSRS (if applicable), MMS Section C and BPRS (if applicable), MPSS-2, MNWS, 
PSS-4, STAI, CES-D, PSQI and mCEQ. Participants will also complete expired CO and salivary cotinine testing and have 
their blood pressure, heart rate and weight measured. Urine will also be collected to test for AXS-05. The CRC who is 
not blinded will handle the delivery of the urine samples to LabCorp. Only urine samples from those randomized into 
the AXS-05 arms will be sent to LabCorp for DXM testing.  Because only study subjects and not controls will be tested 
for urine DXM, Lab Corp will be instructed to send urine DXM results to the attention of the CRC.  The CRC will keep 
the results of the DXM testing private and secure so that blinded personnel do not see it. The CRC will make the urine 
DXM results available at the end of the study once the blind is removed.  
Subjects will also complete a Medications Side Effects Log and discuss any side effects with Physician or PA at the 
next visit. Subjects will be given a supply of study medications to use for one week (+ 5 days in case of a missed visit). 
Subjects will also be given diaries to record medication use, irritability, urges, and the number of cigarettes smoked 
each day and will be instructed to return the diaries at the next visit. Participants will be asked to bring all remaining 
medications to every visit.  Remaining medications will be reconciled with medication use data in participant diaries.  
Participants will be instructed not to “double dose” and not to take medications to “catch up,” but only to take 
medications at specified times (1 pill before breakfast and 1 pill before dinner).  At the end of the study, any unused 
medications will be collected and destroyed.  
Visit 3 (2-Week Follow-up Visit) 
The third visit (also referred to as (2 Week Follow-up Visit)) will take place approximately one week after Visit 2. 
Subjects will complete repeated questionnaires and tests. Repeated questionnaires include: Recent Smoking 
Questionnaire, PHQ-9 Question 9 and C-SSRS (if applicable), MMS Section C and BPRS (if applicable), MPSS-2, MNWS, 
PSS-4, STAI, CES-D, PSQI and mCEQ. Participants will also complete expired CO and salivary cotinine testing and have 
their blood pressure, heart rate and weight measured. 
Subjects will also complete a Medications Side Effects Log and discuss any side effects with Physician or PA at the 
next visit. Subjects will be given a supply of study medications to use for one week (+ 5 days in case of a missed visit). 
Subjects will also be given diaries to record medication use, irritability, urges, and the number of cigarettes smoked 
each day and will be instructed to return the diaries at the next visit. They will also be asked to return any unused 
medications for proper disposal and compliance monitoring. Urine will also be collected to test for AXS-05. The CRC 
who is not blinded will be handling the delivery of the urine samples to LabCorp. Only urine samples from those 
randomized into the AXS-05 arms will be sent to LabCorp for DXM testing. 
Visit 4 (3-Week Follow-up Visit) 
The fourth visit (also referred to as (3 Week Follow-up Visit)) will take place approximately one week after Visit 3. 
Subjects will complete repeated questionnaires and tests. Repeated questionnaires include: Recent Smoking 
Questionnaire, PHQ-9 Question 9 and C-SSRS (if applicable), MMS Section C and BPRS (if applicable), MPSS-2, MNWS, 
PSS-4, STAI, CES-D, PSQI and mCEQ. Participants will also complete expired CO and salivary cotinine testing and have 
their blood pressure, heart rate and weight measured. 
Subjects will also complete a Medications Side Effects Log and discuss any side effects with Physician or PA at the 
next visit. Subjects will be given a supply of study medications to use for one week (+5 days in case of missed visit). 


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Subjects will also be given diaries to record medication use, irritability, urges, and the number of cigarettes smoked 
each day and will be instructed to return the diaries at the next visit. They will also be asked to return any unused 
medications for proper disposal and compliance monitoring. Urine will also be collected to test for AXS-05. The CRC 
who is not blinded will be handling the delivery of the urine samples to LabCorp. Only urine samples from those 
randomized into the AXS-05 arms will be sent to LabCorp for DXM testing. 
Starting at midnight of the day of Visit 4, Participants will receive instructions to not smoke over the following 7 days. 
Abstinence will be validated by self-report, expired CO, and salivary cotinine at Visit 5. If participants are self-report 
and biochemically validated as abstinent, they will receive an additional $70 in compensation at Visit 5. 
Visit 5 (4-Week Follow-up Visit) 
The fifth visit (also referred to as 4-Week Follow-up Visit) will take place approximately one week after Visit 4. 
Subjects will complete repeated questionnaires and tests. Repeated questionnaires include: Recent Smoking 
Questionnaire, PHQ-9 Question 9 and C-SSRS (if applicable), MMS Section C and BPRS (if applicable), MPSS-2, MNWS, 
PSS-4, STAI, CES-D, PSQI and mCEQ. Participants will also complete expired CO and salivary cotinine testing and have 
their blood pressure, heart rate and weight measured. Urine will also be collected to test for AXS-05. The CRC who is 
not blinded will be handling the delivery of the urine samples to LabCorp. Only urine samples from those randomized 
into the AXS-05 arms will be sent to LabCorp for DXM testing. 
Subjects will also complete a Medications Side Effects Log and discuss any side effects with Physician or PA at the 6-
Week Phone Call. 
6-Week Phone Call:    
The 6-week Phone Call will take place approximately 2 weeks after the last scheduled study visit (Visit 5) for 
participants completing the study. If a participant drops out of the study early, this call will be placed approximately 2 
weeks after the last study visit they attended.  If the participant experiences an Adverse Event (AE), the call will be 
placed approximately 2 weeks after the resolution of the AE (whichever comes last). This call will occur by phone for 
all subjects. The purpose of this call is to assess the presence of any side effects following the end of treatment and 
current smoking status (Appendix 17, Appendix 29). At Visit 5 participants will be provided with the End of Treatment 
Follow-Up Side Effects Questionnaire (Appendix 17). At the 6-week Follow-up Phone Call, participants will be asked 
to review this questionnaire. They will also be asked to rate the severity of the side effect (1-not at all severe to 7-
extremely severe) as well as its frequency (from “Just once” to “More than once a day”). If concerns arise during the 
phone call, the call will be transferred to the Study Physician/PA for management.  In addition, the Study 
Physician/PA will review this questionnaire and contact the participant if there are concerns.  An example of the End 
of Treatment Follow-Up Side Effects Questionnaire can be found in Appendix 17. Additionally, the subject will be 
asked to answer PHQ-9 Question 9 and if positive the C-SSRS assessment, as well as Section C of the Modified Mini 
Screen and if positive the BPRS assessment.  
10.3. END OF TREATMENT 
Visit 5, which is the 4-week Follow Up visit, will be the End of Treatment.  
10.4. FOLLOW-UP PERIOD 
After Visit 5, a 6 week follow-up phone call will occur. This follow-up, referred to as the “6-Week- Phone Call,” will 
take place approximately 2 weeks after the last scheduled study visit for participants completing the study, 2 weeks 
after participants who dropped out prior to study completion, or until all AEs are resolved (whichever comes later). 
This visit will occur over the phone for all subjects. Participants will be asked to return all unused medications at each 
visit. Participants who are concerned with side effects will be instructed to call the Center for Smoking Cessation. The 
CRS will report to the Physician/PA any reported side effects. Additionally, the subject will be asked to answer PHQ-9 
Question 9 and if positive the C-SSRS assessment, as well as Section C of the Modified Mini Screen and if positive the 


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BPRS assessment. The follow up period for participants to call the study with side effects or other concerns will last 
for two weeks after Visit 5.   
10.5. END OF STUDY 
Study participation will end with each participant after the 6-Week Phone Call. If participants can not be reached by 
phone, they will be listed as “lost to follow-up” for purposes of analysis of results. If participants express interest in 
tobacco use treatment, a referral will be made to the Duke Smoking Cessation Program or other resources for further 
support. After all participants have completed the study, the study data collection period will be considered over and 
the team will begin analysis of results. 
10.6. EARLY WITHDRAWAL OF SUBJECT(S) 
10.6.1. 
CRITERIA FOR EARLY WITHDRAWAL 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject from the study at 
any time based on his/her discretion. Reasons for PI-initiated withdrawal may include, but is not limited to the 
following: 
• 
Adverse events 
• 
Abnormal laboratory values 
• 
Abnormal test procedure results 
• 
Patient Compliance 
• 
Protocol deviation 
• 
Administrative issues 
• 
Disease progression 
• 
Pregnancy 
10.6.2. 
FOLLOW-UP REQUIREMENTS FOR EARLY WITHDRAWAL 
If a participant has cause for premature withdrawal, or if the PI decides that the participant should withdraw, he or 
she will be asked to attend a Premature Withdrawal Visit. If this occurs before Visit 5 (final treatment visit), the 
Premature Withdrawal Visit will essentially mirror Visit 5 (if the subject is able). At this visit all medication will be 
collected and no further medication will be dispensed to the participant.  
10.6.3. 
 REPLACEMENT OF EARLY WITHDRAWAL(S) 
Subjects who withdraw, do not complete at least three weeks of assessments, or are lost to follow-up will be 
replaced in order to reach a total of N=60 randomized participants included in the analysis.  It is anticipated that 
approximately 66 subjects will be enrolled into the study.   
10.7. STUDY ASSESSMENTS 
10.7.1. 
 MEDICAL HISTORY 
Medical history assessments will be completed by each subject. This assessment will include questions about any 
significant medical diagnoses, recent hospitalizations, surgeries, family history, social history, and medication use. 
Appendix 2 provides an overview of medical history information to be collected and is considered a baseline 
measure.   
10.7.2. 
 PHYSICAL EXAM 
At the screening visit, a study physician or PA will conduct a physical exam of the participant for general health. 
Abnormal findings during the exam can be used to exclude participants from the study. An EKG will also be 
performed as part of the exam.  
10.7.3. 
EXHALED CARBON MONOXIDE BREATH TEST 
The Exhaled Carbon Monoxide Breath Test will be used as objective confirmation of participant-reported number of 
cigarettes smoked per day. Exhaled Carbon Monoxide Breath testing will be evaluated at Screening, Baseline, 1 week, 


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2 week, 3 week, and 4 week Follow Up Visits. Values less than 7 ppm are considered abstinent (96.0% sensitivity and 
93.3% specificity).72 
10.7.4. 
SALIVARY COTININE TEST 
Salivary Cotinine test will be used as an additional objective confirmation of participant-reported number of 
cigarettes smoked per day. Salivary cotinine will be tested at the baseline, 1 week, 2 week, 3 week, and 4 week visits, 
with a cutoff of < 13 ng/ml to define abstinence (sensitivity, 86.5%; specificity, 95.9%)73.  
10.7.5. 
PATIENT HEALTH QUESTIONNAIRE (PHQ-9) 
The Patient Health Questionnaire PHQ-9 for Depression (Appendix 3) will be used to screen for current (within 2 
weeks) depression at the Screening Visit. Participants who have scores of zero or higher on question 9 (suicidality) 
will be excluded from the study62. Patients with severe and symptomatic depression may also be excluded based on 
physician/PA discretion. 
10.7.6. 
GENERALIZED ANXIETY DISORDER (GAD-7) 
Anxiety will be assessed using the GAD-7 (Appendix 4) at the Screening Visit. The measure will be used to exclude 
participants from the study who have severe symptomatic anxiety based on study physician/PA discretion76.  
10.7.7. 
SMOKING HISTORY 
At the screening visit, the subject will complete the Smoking History questionnaire (Appendix 5). This non-
standardized, 10-item questionnaire provides information on the number of pack years, social support, additional 
tobacco product use, and other drug use. 
10.7.8. 
FAGERSTROM TEST FOR NICOTINE DEPENDENCE (FTND) 
The FTND (Appendix 6) is a validated measure consisting of 6 items that assess a participant’s level of physical 
nicotine dependence. The FTND will be administered at the Screening Visit.  
10.7.9. 
RECENT SMOKING QUESTIONNAIRE 
At the baseline, 1 Week, 2 Week, 3 Week, and 4 Week Follow-up Visits a participant’s recent smoking habits will be 
assessed using the Recent Smoking Questionnaire (Appendix 7). This non-standardized questionnaire provides 
information about the participants smoking behavior over the last 7 days.  
10.7.10. 
SCREENING VISIT SMOKING DIARY 
At the Screening Visit subjects will be given a diary (Appendix 8) to complete with the number of cigarettes smoked 
per day from the day of the screening until Visit 1. This will be used to establish baseline information on cigarettes 
smoked per day. 
10.7.11. 
7-DAY SMOKING CESSATION PROTOCOL 
Subjects are asked not to smoke at all during a 7 day period between Visit 4 and 5. Smoking abstinence will be tested 
in this protocol using self-reported total abstinence with biochemical confirmation via expired air carbon monoxide 
(CO) breath test < 7ppm (96.0% sensitivity and 93.3% specificity)72 and salivary cotinine with a cutoff of < 13 ng/ml to 
define abstinence (sensitivity, 86.5%; specificity, 95.9%)73.  
10.7.12. 
 SMOKING, MEDICATION USE, URGE AND IRRITABILITY DIARY 
Participants will be given a diary that will assess their cigarette use, medication adherence, urges, and irritability 
throughout the study. The diary will be given at the Baseline Visit and will be collected and reviewed at the 1 Week, 2 
Week, 3 Week, and 4 Week Follow-up Visits. Any omissions will be reviewed with the participant by study staff and 
every effort will be made to obtain accurate and complete diary data. A sample diary can be found in Appendix 9. 
10.7.13. 
 MEDICATION SIDE EFFECTS QUESTIONNAIRE 
Participants will be asked in-person at the 1 Week, 2 Week, 3 Week, and 4 Week Follow-up Visits about any 
medication side effects they have been experiencing. Participants will also be asked about any side effects they have 


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been experiencing following the end of treatment at the 6-Week Phone Call. Participants will be asked if there are 
any side effects that they are experiencing. They will be asked to rate the severity of the side effect (1- not at all 
severe to 7-extremely severe) as well as its frequency (From “Just once” to “More than once a day”). The CRS as well 
as the Study Physician/PA will review this form. An example of the Medication Side Effects Questionnaire can be 
found in Appendix 10. 
10.7.14. 
 MOOD AND PHYSICAL SYMPTOMS SCALE (MPSS-2) 
The Mood and Physical Symptoms Scale is a two question scale to assess urges to smoke over a 24 hour period. It will 
be administered at the 1 Week, 2 Week, 3 Week, and 4 Week Follow-up Visits. The MPSS-2 can be found in Appendix 
11.  
10.7.15. 
 STATE-TRAIT ANXIETY INVENTORY (STAI)70 
The State-Trait Anxiety Inventory is a 40 item introspective measure developed to assess both trait and state anxiety. 
The STAI will be administered at the 1 Week, 2 Week, 3 Week, and 4 Week Follow-up Visits. These assessment time 
points will help assess overall levels of anxiety as well as situation-based anxiety. The STAI can be found in Appendix 
12.  
10.7.16. 
 CENTER FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE-REVISED (CESD-
R)71 
The Center for Epidemiologic Studies Depression Scale-Revised is a 20 item scale that asks participants to rate how 
often they have had symptoms of depression (following the DSM-V). The scale will be administered at the 1 Week, 2 
Week, 3 Week, and 4 Week Follow-up Visits. The complete CES-D-R can be found in Appendix 13. 
10.7.17. 
 MINNESOTA NICOTINE WITHDRAWAL SCALE (MNWS)69 
The Minnesota Nicotine Withdrawal Symptoms Scale is an 15 item scale that is designed to measure nicotine 
withdrawal symptoms (i.e. craving, irritability, anxiety, difficulty concentrating, restlessness, increased appetite or 
weight gain, depression, and insomnia). The MNSW will be administered at the 1 Week, 2 Week, 3 Week, and 4 Week 
Follow-up Visits. The complete MNSW can be found in Appendix 14. 
10.7.18. 
 PITTSBURGH SLEEP QUALITY INDEX (PSQI)77 
The Pittsburgh Sleep Quality Index is a 19 item scale that was designed to assess the quality and patterns of sleep of 
adults. The PSQI will be administered at the 1 Week, 2 Week, 3 Week, and 4 Week Follow-up Visits. The PSQI can be 
found in Appendix 15. 
10.7.19. 
BRIEF AGITATION MEASURE 
The Brief Agitation Measure is a 3 item scale designed to assess a participants agitation level. Agitation is a common 
symptom of withdrawal, so will help assess overall experiences of withdrawal. The BAM will be administered at the 1 
Week, 2 Week, 3 Week, and 4 Week Follow-up Visits. The BAM can be found in Appendix 16. 
10.7.20. 
MODIFIED MINI SCREEN (SECTION C) 
The Modified Mini Screen is a 7-item scale designed to assess for psychotic disorders. Exclusionary criteria for this 
study includes people with a diagnosis of schizophrenia, so this measure will be used to evaluate eligibility for the 
study at the screening visit. In addition, the MMS (Section C) will be used at each study visit after initiation of the 
study drug to monitor for emerging psychosis, as Bupropion can precipitate neuropsychiatric conditions including 
psychosis. The MMS can be found in Appendix 20.  
10.7.21. 
MOOD DISORDER QUESTIONNAIRE 
The Mood Disorder Questionnaire is a 15-item scale designed to assess for Bipolar Disorder. Exclusionary criteria for 
this study includes people with a diagnosis of bipolar disorder, so this measure will be used to evaluate eligibility for 
the study at the screening visit. The MDQ can be found in Appendix 19.  


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10.7.22. 
SCOFF QUESTIONNAIRE 
The SCOFF questionnaire is a 5-item scale designed to screen for eating disorders. Anorexia and Bulimia are 
contraindications to the use of Bupropion, so a diagnosis of these eating disorders will be exclusionary for this study. 
The SCOFF will be assessed at the screening visit, and can be found in Appendix 18. 
10.7.23. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment. It assesses 
suicidal ideation, intensity of ideation, and suicidal behavior. Participants will be assess for suicidality using the PHQ-9 
question 9 (Appendix 3) at each visit after initiation of the study drug. If a participant scores >0 on this question, the 
study clinician will immediately be contacted and the C-SSRS will be used for further clinical assessment and follow-
up as needed. The C-SSRS can be found in Appendix 21. 
10.7.24. 
BRIEF PSYCHIATRIC RATING SCALE (BPRS) 
The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered instrument used for assessing positive, negative 
and affective symptoms for psychotic disorders over 18 symptom constructs. Participants will be assessed for 
psychotic disorders using the MMS Section C (Appendix 20) at each visit after initiation of the study drug. If a 
participant answers “Yes” to any of the items on the MMS Section C, a study clinician will immediately be contacted 
and the BPRS will be used for further clinical assessment and follow-up as needed. The BPRS can be found in 
Appendix 22. 
10.7.25. 
PERCEIVED STRESS SCALE (PSS-4) 
The Perceived Stress Scale is a 4 item used to measure the perception of stress. Higher PSS scores have been 
associated with lower rates of smoking cessation. The scale will be administered at the 1 Week, 2 Week, 3 Week, and 
4 Week Follow-up Visits. The PSS-4 can be found in Appendix 23. 
10.7.26. 
MODIFIED CIGARETTE EVALUATION QUESTIONNAIRE (MCEQ) 
The Modified Cigarette Evaluation Questionnaire (MCEQ) is a 12 item survey that assesses the rewarding and 
aversive effects of smoking. It will be administered at the 1 week, 2 week, 3 week and 4 week-follow-up visits. The 
mCEQ can be found in Appendix 24. 
10.7.27. 
REVIEW OF SYSTEMS (ROS) 
The Review of systems (ROS) is a list of possible symptoms covering the organ systems. The ROS will be administered 
at the screening visit as part of the medical evaluation to assess for any current symptoms a potential participant is 
experiencing. It can be found in Appendix 27. 
10.7.28. 
AUDIT-C 
Alcohol Use Disorders Identification Test-C is a three-item questionnaire used to screen for people with alcohol use 
disorders. A score of 4 or more for men or 3 or more for women will be considered positive, and will require 
physician discretion to determine if an active alcohol use disorder is present. If it is determined by a clinician that an 
active alcohol use disorder is present, the potential participant will be excluded from the study.. The AUDIT-C will be 
asked during the phone screen. It can be found in Appendix 28. 
 
 
 


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11. SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject or 
evaluation of study assessments, whether an AE or SAE has occurred. 
11.1. ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and which does not 
necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also includes 
worsening of any pre-existing medical condition. An AE can therefore be any unfavorable and unintended or 
worsening sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of study therapy that may or may not be related to use of the study therapy. Abnormal laboratory findings without 
clinical significance (based on the PI’s judgment) should not be recorded as AEs. But laboratory value changes that 
require therapy or adjustment in prior therapy are considered adverse events. 
From the time the subject is randomized through the End of Study visit (as defined in Section 10.3), all AEs must be 
recorded in the subject medical record and adverse events case report form. 
AEs will be assessed according to the CTCAE version 4.0. If CTCAE grading does not exist for an AE, the severity of the 
AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study therapy 
- 
Probably:  The AE is likely related to the study therapy 
- 
Possible:  The AE may be related to the study therapy 
- 
Unlikely:  The AE is doubtfully related to the study therapy 
- 
Unrelated:  The AE is clearly NOT related to the study therapy 
11.1.1. 
AES OF SPECIAL INTEREST 
Adverse Events related to AXS-05 used in prior studies have been minimal and no SAEs have occurred. As such there 
are no adverse events, which will require special attention.   
11.1.2. 
REPORTING OF AES 
During each annual IRB review of the protocol, a list of all AEs will be provided to the IRB for review. This report 
includes whether the AE was likely related to study procedures, whether it impacted subject participation, whether 
the AE was resolved, and any other action taken.   
11.2. SERIOUS ADVERSE EVENTS 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
• 
Fatal 
• 
Life-threatening 
• 
Constitutes a congenital anomaly or birth defect 
• 
A medically significant condition (defined as an event that compromises subject safety or may require 
medical or surgical intervention to prevent one of the three outcomes above) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption to conduct normal life functions 


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11.2.1. 
REPORTING OF SAES 
Life-threatening (grade 4 or 5) SAEs, deaths, and unknown reactions or unexpected events that occur in the course of 
any patient’s treatment of study (from the time of consent) or within 30 days following cessation of treatment are 
reportable. The DCI SAE Report Form and DCI Safety Review Form will be completed and submitted to the IRB per 
standard protocol. The initial report for each SAE or death should include at minimum the following information: 
• 
Protocol # and title 
• 
Patient initials, study identification number, sex, age 
• 
Date the event occurred 
• 
Description of SAE 
• 
Description of patient’s condition 
• 
Indication whether the patient remains of study 
• 
Causality or causal relationship 
De-identified source documentation (i.e. discharge notes) must be sent with the SAE Report Form. Follow-up 
information including severity, action taken, concomitant medications, and outcome should be communicated to 
Duke as soon as possible using the same forms mentioned above. 
As soon as an investigator becomes aware of an AE that meets the definition of serious: 
• 
The Study Coordinator will submit to Axsome Therapeutics or designee within 24 hours of Investigator’s 
awareness, even if it is not felt to be drug related 
• 
The investigator agrees to provide supplementary information requested by Axsome Therapeutics safety 
personnel or designee  
SAEs will be reported by the PI in an expedited manner to the Duke University Health System (DUHS) Institutional 
Review Board (IRB) office, NIDA, and FDA.  
SAEs will be reported to the DUHS IRB using the following timelines: 
• 
24 hours – for an unanticipated study-related death 
• 
1 week (5 business days) – for an unanticipated problem that is a serious adverse event 
• 
2 weeks (10 business days) – for an unanticipated problem that does not meet the criteria of a serious adverse 
event 
SAEs will be reported to the NIDA Serious Adverse Event Tracking and Reporting System (SAETRS) within 72 hours. 
The NIDA Program Official will be kept apprised of IRB actions related to SAEs and any plan to modify the protocol as 
a result of IRB recommendation will be subject to NIDA approval. 
In accordance with applicable regulations, investigators will submit the SAE report to their local IRB according to local 
IRB institutional guidelines. Dr. Davis, the study PI is responsible for reporting the serious adverse event to the FDA in 
accordance with 21 CFR 312.32. Any SAE that is possibly related and unexpected will be reported to the FDA no later 
than 15 calendar days upon notification of the event.  The FDA will be notified of any unexpected fatal or life-
threatening suspected adverse reactions no later than 7 calendar days after notification. This will be done by the 
study coordinator. 
• 
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) completed by the study 
coordinator/DCI. 
• 
The final MedWatch Form must be submitted by the study site to Axsome within one to two business days of 
submission to the FDA. 
11.3. EMERGENCY UN-BLINDING OF INVESTIGATIONAL TREATMENT 
The Clinical Research Coordinator will not be blinded to the treatment. The Principle Investigator as well as the 
Clinical Research Specialist and statistician will be blinded. In the case that Emergency un-blinding is required, the 


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Principle Investigator will contact the Clinical Research Coordinator directly to obtain the necessary information. 
Emergency contact information for un-blinding will be the email and cell phone number of Leah Thomas, the study 
CRC: leah.thomas@duke.edu, 704-798-4498.   
11.4. OTHER REPORTABLE INFORMATION 
Other reportable information including pregnancy, development of disease, or hospitalization for non-study related 
causes will be reported as AEs or SAEs depending on the severity and assessed as to whether these are related to 
study procedures.    
11.5. SPECIAL WARNINGS AND PRECAUTIONS 
There are no special warnings or precautions for this study. 
11.6. STOPPING RULES 
The study will be stopped prior to its completion if: 1. difficulty in study recruitment or retention will significantly 
impact the ability to evaluate the study endpoints; 2. any new information becomes available during the study that 
necessitates stopping the study; 3. there are significant treatment related toxicities that become evident through the 
course of the study; or 4. other situations occur that might warrant stopping the study.  
11.7. SAFETY OVERSIGHT COMMITTEE (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-investigator 
phase I and II, therapeutic interventional studies that do not have an independent Data Safety Monitoring Board 
(DSMB). The primary focus of the SOC is review of safety data, toxicities, and new information that may affect subject 
safety or efficacy. Annual safety reviews include but may not be limited to review of safety data, enrollment status, 
stopping rules if applicable, accrual, toxicities, reference literature, and interim analysis as provided by the sponsor-
investigator. The SOC in concert with the DCI Monitoring Team (see Section 12.1 for Monitoring Team description) 
oversees the conduct of DUHS cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies 
that do not have an external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded 
and reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), 
and applicable regulatory requirements. The DCI Safety Oversight Committee (SOC) will perform annual reviews on 
findings from the DCI Monitoring Team visit and additional safety and toxicity data submitted by the Principal 
Investigator. 
11.8. EXTERNAL DATA AND SAFETY MONITORING BOARD (DSMB) 
DSMBs are usually advised for Phase III multi-center clinical trials in which study participants are exposed to 
substantial risk or vulnerable populations are studied. This study, however, will be conducted at only one study site in 
Durham, North Carolina. Based on extensive clinical experience with bupropion and dextromethorphan as separate 
medications as well as recent trials on combined Dextromethorphan-Bupropion (AXS-05) demonstrating good 
medication tolerance and a favorable side effect profile, there is no reason to expect significant risks to subjects. 
Additionally, vulnerable populations will not be studied in this protocol. Hence, we have concluded that oversight by 
the scientific and medical team will be adequate for this study and that a formal DSMB will not be needed. 
 
 
 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. MONITORING 
This clinical research study will be monitored both internally by the PI and institutionally by the Duke Cancer Institute 
(DCI).  In terms of internal review, the PI will continuously monitor and tabulate adverse events.  Appropriate 
reporting to the Duke University Medical Center IRB will be made.  If an unexpected frequency of Grade III or IV 
events occur, depending on their nature, action appropriate to the nature and frequency of these adverse events will 
be taken.  This may require a protocol amendment, dose de-escalation, or potentially closure of the study.  The PI of 
this study will also continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
• 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety 
Monitoring Plan.   
Briefly, protocol review begins with an initial review by the Cancer Protocol Committee (CPC), which assesses the 
ethics and safety of the protocol.  Documentation of these assessments will be maintained.  Formal, independent 
monitoring will be conducted by the DCI Monitoring Team after the first 3 subjects are enrolled, followed by annual 
monitoring of 1-3 subjects until the study is closed to enrollment and subjects are no longer receiving study 
interventions that are more than minimal risk.  DCI Monitoring Team reports and additional data/safety/toxicity 
reports submitted by the PI will be reviewed by the Safety Oversight Committee (SOC) on an annual basis.  Additional 
monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected 
toxicities, or other concerns.  Monitoring visits may also be initiated upon request by DUHS and DCI Leadership, CPC, 
SOC, a sponsor, an investigator, or the IRB.     
12.2. AUDITS 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct confidential audits to 
evaluate compliance with the protocol and the principles of GCP. The PI agrees to allow the CTQA auditor(s) direct 
access to all relevant documents and to allocate his/her time and the time of the study team to the CTQA auditor(s) 
in order to discuss findings and any relevant issues. 
CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA audits may be 
routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared towards high 
subject enrollment, studies with limited oversight or monitoring, Investigator-initiated Investigational Drugs or 
Devices, federally-funded studies, high degree of risk (based upon adverse events, type of study, or vulnerable 
populations), Phase I studies, or studies that involve Medicare populations. Directed audits occur at the directive of 
the IRB or an authorized Institutional Official. 
CTQA audits examine research studies/clinical trials methodology, processes, and systems to assess whether the 
research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the audit/review 
is to verify that the standards for safety of human subjects in clinical trials and the quality of data produced by the 
clinical trial research are met. The audit/review will serve as a quality assurance measure, internal to the institution. 
Additional goals of such audits are to detect both random and systemic errors occurring during the conduct of clinical 
research and to emphasize “best practices” in the research/clinical trials environment. 


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12.3. DATA MANAGEMENT AND PROCESSING 
12.3.1. 
CASE REPORT FORMS (CRFS) 
The electronic and paper CRF will be the primary data collection document for the study. The CRFs will be updated in 
a timely manner following acquisition of new source data. Only approved study staff including the PI, PA, and CRS are 
permitted to make entries, changes, or corrections in the CRF. 
Errors will be crossed out with a single line, and this line will not obscure the original entry. Changes or corrections 
will be dated, initialed, and explained (if necessary). The PI or authorized key personnel will maintain a record of the 
changes and corrections. 
An audit trail will be maintained automatically by the electronic CRF management system REDCap. Designated 
personnel will complete user training, as required or appropriate per regulations. 
12.3.2. 
DATA MANAGEMENT PROCEDURES AND DATA VERIFICATION 
Designated personnel using the electronic CRF will have access based on their specific roles in the protocol. The PI, 
PA, and CRS will have access. 
Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the 
presence of data inconsistencies. Additionally, the CRC will cross-reference the data to verify accuracy. Missing or 
implausible data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of 
data, completion or confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of all 
remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
12.3.3. 
STUDY CLOSURE 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 
 
 
 


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13. STATISTICAL METHODS AND DATA ANALYSIS  
All statistical analysis will be performed under the direction of the statistician designated in key personnel. Any data 
analysis carried out independently by the investigator must be approved by the statistician before publication or 
presentation. 
13.1. ANALYSIS SETS 
Dataset will be collected through five visits: the Baseline Visit and four weekly study visits. Data will include 
information from self-report, diaries, and objective tests of urine, saliva, and expired CO. All data measures will be 
captured using REDCap78, an encrypted, HIPAA compliant, data collection system. Data entry is time-stamped for use 
in calendar-based assessment visits with capacity for upload into statistical programs Excel, Statview, SAS, SPSS, 
MPlus, and R. Trained Duke staff will conduct data integrity processes for REDCap data78. 
13.2. PATIENT DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Participants will be adult smokers recruited through the Duke Center for Smoking Cessation   
13.3. TREATMENTS 
Drug Dose: Smokers will be randomized with 1:1 allocation to AXS-05 (45 mg Immediate Release DXM + 105 mg 
Sustained Release BUP) vs. 105 mg Sustained Release BUP. Medications will be provided to participants at the 
Baseline Study Visit and continued for four weeks in each group.   
Study Group Dosing:  Dextromethorphan Immediate Release 45mg + Bupropion Sustained Release 105 mg  
Dose Timing Administration: For the first three days, take one tablet in the morning on an empty stomach (one hour 
prior to the morning meal or two hours after the morning meal). Thereafter take one tablet two times per day, on an 
empty stomach, at least 8 hours apart and 1 hour prior to a meal, or 2 hours after a meal. 
Control Group: Bupropion Sustained Release 105 mg 
Dose Timing Administration: For the first three days, take one tablet in the morning on an empty stomach (one hour 
prior to the morning meal or two hours after the morning meal). Thereafter take one tablet two times per day, on an 
empty stomach, at least 8 hours apart and 1 hour prior to a meal, or 2 hours after a meal. 
13.4. PRIMARY OBJECTIVE 
To evaluate the impact of AXS-05 compared to BUP on change in smoking intensity from baseline to the 3-Week 
Follow-Up Visit.  Smoking intensity, refers to the total amount of smoke inhaled by the smoker and includes number 
of cigarettes smoked per day. Smoking intensity will be assessed as a latent variable modeled through three 
predictive factors: 1. Salivary cotinine which will be assessed at all study visits. 2. Expired carbon monoxide (CO) 
breath testing at all study visits and 3. Number of cigarettes smoked per day assessed via daily smoking diaries. 
Because salivary cotinine and CO are measured at weekly intervals, weekly means of cigarettes smoked per day will 
be calculated for each participant and used in the latent variable analysis.   
13.4.1. 
VARIABLES 
Cigarettes smoked per day, expired CO, salivary cotinine  
13.4.2. 
STATISTICAL HYPOTHESIS, MODEL, AND METHOD OF ANALYSIS 
Testing for our primary hypotheses will be based on use of smoking intensity as a latent variable constructed through 
modeling of 3 predictor variables – salivary cotinine, CO, and the number of cigarettes smoked per day. These 
variables will be assessed for the development of composite measure of smoking intensity through latent variable 
modeling.  Modeling of primary outcomes in this way is expected to provide a more powerful and accurate 
assessment of smoking behavior by minimizing measurement error. Latent variable structure will be developed using 
established methods, with fit of the measurement model (i.e., latent variable) determined using standard fit criteria: 
standardized root mean square residual (SRMR) < .05, root mean square error of approximation (RMSEA) < .08, and 


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comparative fit index (CFI) > .90. The chi-squared test of model fit will also be consulted, with non-significance 
indicative of good model fit.  
For some comparisons conducted in this study, logistic regression models will be assessed for computation of odds 
ratio (OR) estimates and confidence intervals (CIs). All analyses will follow an intent-to-treat approach with alpha 
criterion of 0.05 in comparisons. Given repeated observations across multiple individuals and time points, many of 
the analyses in this study will be derived from multilevel modeling (MLM). MLM hierarchically organizes data as a 
function of person-specific variables and time-point specific variables. Unlike repeated-measures ANOVA, MLM is 
able to handle data distributions with unequal variances across time points and individuals79. In addition to modeling 
between-person differences, MLM is also able to model within-person variability in variables that change over time. 
Because MLM procedures are based on maximum likelihood estimation and use all available data, MLM can 
accommodate missing data at random and is often considered favorable to multiple imputation techniques, which 
can yield varied results depending on the imputation model80, 81.   
Multilevel structural equation modeling (MSEM) will be used to test the primary hypothesis that participants in the 
study group will demonstrate decreased smoking intensity post-baseline relative to the control group. Specifically, 
the aforementioned smoking intensity latent variable will be modeled at the baseline, 1-week follow-up, 2-week 
follow-up, and 3-week follow-up as a function of treatment group and time of assessment, with the baseline 
assessment treated as the reference group. Treatment X Time interactions will additionally be explored to determine 
whether the two treatments are associated with distinct trajectories of smoking intensity. Linear contrasts within the 
context of the model will be derived to estimate point differences in smoking intensity between the treatment 
groups at the 3-week follow-up. 
13.4.3. 
HANDLING OF MISSING VALUES, CENSORING, AND DISCONTINUATIONS 
Missing data will be examined to determine whether missingness is systematic or at random. To manage the problem 
of random positive findings when making multiple comparisons82, 83 (e.g. random significant findings occurring due to 
multiple proposed analyses), we will correct alpha by using the false discovery rate approach described by 
Glickman84. This methodology differentiates random findings from hypothesis-driven outcomes and is more powerful 
than Bonferroni-type alpha adjustments that control the false positive rate79, 81, 82, 83, 85.  
13.5. SECONDARY OBJECTIVES 
Secondary Objectives (Smoking Behavior) 
1. 
To compare AXS-05 to BUP on smoking abstinence within a 7-day Abstinence Test conducted between the 3-
week and 4-Week Study Visits. Smoking Abstinence and approximate time of lapse will be assessed by self-
report diaries and biochemically confirmed via expired CO and salivary cotinine.   
Secondary Objectives (Covariates and Potential Moderators) 
2. 
To assess specific baseline variables for an association with smoking behavior outcome, listed above. Baseline 
variables assessed will include age, gender, race, education, baseline nicotine dependence, stress, anxiety, 
depression, and self-efficacy. If a baseline variable is found to be associated with change in smoking behavior, 
it will be treated as a covariate in a secondary analysis of smoking behavior and assessed as a potential 
moderator of treatment effect.  
Secondary Objectives (Adherence, Side Effects, and Tolerance)  
3. 
To compare AXS-05 to BUP on adherence to self-administered drug through Medication Use diaries  
4. 
To compare AXS-05 to BUP on tolerability through weekly, open-ended survey to assess potential side 
effects.  
5. 
To compare AXS-05 to BUP on the incidence of adverse events or serious adverse events utilizing FDA 
accepted reporting guidelines on these outcomes.   
Secondary Objectives (Pharmacokinetics)  


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6. 
To measure urine drug levels of DXM at weeks 1-4 and assess potential associations of these levels with 
smoking behavior and side effects.  
Secondary Objectives (Potential Mediators)  
7. 
To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: 
smoking urges, withdrawal symptoms, smoking reward, stress, anxiety, depression, sleep disturbance, and 
agitation.. 
8. 
To compare AXS-05 to BUP on change from baseline to weeks 1-4 on daily assessment of the following: urge 
frequency, urge severity, and irritability.  
 
13.5.1. 
KEY SECONDARY OBJECTIVE ANALYSIS  
1. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate a significantly higher abstinence rate during 
the 7 day abstinence test between the week 3 and week 4 Study Visits assessed via self-reported abstinence 
with biochemical confirmation using expired CO breath testing and salivary cotinine.  Testing of this will be 
based on chi-square test of the difference in abstinence between AXS-05 and active with logistic regression 
used to compute odds ratio (OR) estimates and confidence intervals (CIs). Survival analysis of time to lapse as 
a function of treatment will be analyzed using Cox regression86. Participants who remain abstinent through 
the end of the 7-day Abstinence Test will be censored, meaning that a time of lapse is unavailable. 
Nevertheless, the number of censored participants per group will contribute to the respective hazard ratios 
estimated for each group. The proportional-hazards assumption (that the relative hazard of lapse will remain 
constant within each treatment group over time) will be tested via examination of Schoenfeld residuals87. It is 
hypothesized that participants receiving AXS-05 will be slower to lapse than participants receiving BUP. 
 
13.5.2. 
OTHER SECONDARY OBJECTIVES 
Secondary Hypotheses (Covariates):  
1. 
Potential baseline predictors of tobacco use will not be associated with smoking behavior outcomes listed in 
objectives 1-6; these predictors include age, gender, race, education, baseline nicotine dependence, stress, 
anxiety, depression, and self-efficacy (motivation). Logistic regression models will assess group differences in 
the change in smoking rates controlling for demographic variables (e.g., age, sex, race) and baseline 
covariates known to predict abstinence (e.g., nicotine dependence). 
Secondary Hypotheses (Adherence, Side Effects, and Tolerance)  
2. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference on adherence to 
self-administered drug via Medication Use Diaries.  This will be tested using non-inferiority testing through 
use of the two one-sided tests procedure (TOST) with determination of the equivalence margin, δ, with f of 
0.5088.  
3. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference in spontaneous self-
reported side effects.  This will be tested using non-inferiority testing through use of the two one-sided tests 
procedure (TOST) with determination of the equivalence margin, δ, with f of 0.5088.  
4. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate no significant difference on adverse events 
or serious adverse events utilizing FDA accepted reporting guidelines on these outcomes.  This will be tested 
using non-inferiority testing through use of the two one-sided tests procedure (TOST) with determination of 
the equivalence margin, δ, with f of 0.5088.  
 
Secondary Hypotheses (Pharmacokinetics)  
5. 
Participants allocated to AXS-05 vs. BUP alone will demonstrate the following with regard to urine drug levels 
at the two and three week visit:  


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A. Relatively stable urine drug levels of DXM (< 50% below or above the mean). This will be assessed using 
descriptive statistics.  
B. A majority of participants will show urine DXM concentrations that are in the “expected therapeutic 
range” for tobacco dependence treatment (30 ng/ml). This will be assessed using descriptive statistics. 
C. There will be an association between DXM levels and smoking behavior outcomes MSEM will be used to 
model the previously described smoking intensity latent variable at weeks 1-4 as a function of urine levels of 
DXM measured at those time points.  
D. Urine levels of DXM will not be associated with a higher incidence side effects or adverse events 
(objectives 9-11). To examine the association of urine levels of DXM with side effects, number of days of 
reported side effects will be summarized at weeks 1-4 for each participant. These numbers will then be 
modeled (likely as a negative binomial distribution) via MLM as a function of urine levels of DXM.  We will 
also examine whether urine levels of DXM that are above the sample mean will be associated with a higher 
incidence of side effects or adverse events. 
Secondary Hypotheses (Potential Mediators)  
6. 
In comparison to participants allocated to BUP, participants allocated to AXS-05 will demonstrate the 
following:  
A. A significant reduction in smoking urges and withdrawal symptoms from baseline to all four post-drug 
initiation time points. MLM will be used to model each of the above variables as a function of treatment 
group and time (baseline, weeks 1-4). Potential Treatment X Time effects will be explored to determine 
whether the two treatments are associated with distinct trajectories of change in the above outcomes. Linear 
contrasts within the context of the model will be derived to estimate point differences in the outcome 
variables between the treatment groups at the 3-week follow-up. 
B. The change in in smoking urges and withdrawal symptoms will be significantly associated with change in 
smoking behavior assessed through the primary objective, independent of treatment group.  MSEM will be 
used to model the smoking intensity latent variable as a function of smoking urges and withdrawal 
symptoms, with treatment group and time (baseline, weeks 1-4) covaried. Potential Treatment X Time effects 
will be examined to determine whether the two treatments are associated with distinct trajectories of 
change in the behavioral and psychological outcomes. It is predicted that smoking urges and withdrawal 
symptoms will exert an effect on smoking intensity independent of treatment or Treatment X Time effects. 
Multicollinearity between each of the psychiatric variables will be examined and their independent effects as 
well as their joint effects will be tested. Pending evidence of mediation, indirect effects will be examined 
both independently and jointly. Multilevel analyses will be conducted using Mplus 7.   
7. 
In comparison to participants allocated to BUP, participants allocated to AXS-05 will demonstrate the 
following:  
A. A significant reduction in stress, anxiety, depression, and withdrawal symptoms and an increase in self-
efficacy and sleep quality from baseline to all four post-drug initiation time points. MLM will be used to 
model each of the above variables as a function of treatment group and time (baseline, weeks 1-4). Potential 
Treatment X Time effects will be explored to determine whether the two treatments are associated with 
distinct trajectories of change in the above outcomes. Linear contrasts within the context of the model will 
be derived to estimate point differences in the outcome variables between the treatment groups at the 3-
week follow-up. 
B. The change in these constructs will be associated with change in smoking behavior assessed through the 
primary objective. MSEM will be used to model the smoking intensity latent variable as a function of the 
above potential mediators, with treatment group and time (baseline, weeks 1-4) covaried. Potential 


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Treatment X Time effects will be examined to determine whether the two treatments are associated with 
distinct trajectories of change in the behavioral and psychological outcomes. It is predicted that smoking 
urges and withdrawal symptoms will exert an effect on smoking intensity independent of treatment or 
Treatment X Time effects. Multicollinearity between each of the psychiatric variables will be examined and 
their independent effects as well as their joint effects will be tested. Pending evidence of mediation, indirect 
effects will be examined both independently and jointly. Multilevel analyses will be conducted using Mplus 7.   
13.6. EXPLORATORY OBJECTIVES 
There are no exploratory objectives.  
13.6.1. 
KEY EXPLORATORY OBJECTIVE 
N/A 
13.6.2. 
OTHER EXPLORATORY OBJECTIVES 
N/A 
13.7. INTERIM ANALYSIS 
Quality Control Analysis: We plan to conduct an interim analysis on de-identified data after a total of 10 subjects (5 
in each group) complete Visit 5 (final visit) in the study. The study blind will not be broken for this analysis and as 
such it will not be known to which arm participants are allocated. This analysis will provide descriptive statistical 
assessments relevant to primary and secondary outcomes.  This analysis will be conducted for the purpose of 
assessing the quality of our testing procedures, data collection, data storage etc.  Because the study blind will not be 
broken, this analysis will not provide meaningful information on primary study outcomes.  Data outcomes of this 
analysis will be shared with the PI but will not be shared with the funding agent (Axsome). 
Efficacy Interim Analysis: Please see the additional attachment for the Statistical Analysis Plan (SAP). This will also be 
submitted to the FDA per normal procedures.   
13.8. SAMPLE SIZE CALCULATION 
This is the first time we know of that DXM has been used in a study on human smoking behavior. Thus, the effect size 
of AXS-05 vs. active control is unknown. Our primary outcome is defined as the number of cigarettes smoked per day 
assessed at the 3-week post drug initiation assessment visit. With 60 participants allocated to each arm of the study, 
we will have at a minimum 80% power to detect an effect equivalent to Cohen’s d = 0.52. However, via the use of 
repeated-measures data, the proposed analysis will likely be sensitive to detect even smaller effects. The finding of 
spontaneous reduction of smoking period most closely parallels our finding of spontaneous reduction in nicotine self-
administration in rats (who do not set a quit day or apply will power to bare on outcomes). Within the rat model, Dr. 
Ed Levin showed a reduction from 18 self-administrations to only 6 per day, a 66% reduction in use.  
 
 
 


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14. ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1. REGULATORY AND ETHICAL COMPLIANCE 
This protocol was designed and will be conducted and reported in accordance with the International Conference on 
Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and 
applicable federal, state, and local regulations. 
14.2. DUHS INSTITUTIONAL REVIEW BOARD AND DCI CANCER PROTOCOL COMMITTEE 
The protocol, informed consent form, advertising material, and additional protocol-related documents must be 
submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for review. The 
study may be initiated only after the Principal Investigator has received written and dated approval from the CPC and 
IRB. 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments 
and changes to the informed consent form. The CPC should be informed about any protocol amendments that 
potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion 
criteria, agent administration, statistical analysis, etc.).  
The Principal Investigator must obtain protocol re-approval from the IRB within one year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within one year of the most 
recent IRB approval, for as long as the protocol remains open to subject enrollment. 
14.3. INFORMED CONSENT 
The informed consent form must be written in a manner that is understandable to the subject population. Prior to its 
use, the informed consent form must be approved by the IRB. 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the 
research, methods, potential risks and benefits, subject concerns, and other study-related matters. This discussion 
will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of coercion. 
Appropriate accommodations will be made available for potential subjects who cannot read or understand English or 
are visually impaired. Potential subjects will have the opportunity to contact the Principal investigator or authorized 
key personnel with questions, and will be given as much time as needed to make an informed decision about 
participation in the study. 
Before conducting any study-specific procedures, the Principal Investigator must obtain written informed consent 
from the subject or a legally acceptable representative. The original informed consent form will be stored with the 
subject’s study records, and a copy of the informed consent form will be provided to the subject. The Principal 
Investigator is responsible for asking the subject whether the subject wishes to notify his/her primary care physician 
about participation in the study. If the subject agrees to such notification, the Principal Investigator will inform the 
subject’s primary care physician about the subject’s participation in the clinical study. 
14.4. STUDY DOCUMENTATION 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring logs, 
appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory 
documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is not limited to signed 
protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory 
certifications, and clinical supplies receipts and distribution records. 
Source documents are original records that contain source data, which is all information in original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 


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instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical trial. When possible, the original record should be 
retained as the source document.  However, a photocopy is acceptable provided that it is a clear, legible, and an 
exact duplication of the original document. 
An electronic case report form (CRF) will be the primary data collection document for the study. The CRFs will be 
updated within two weeks of acquisition of new source data. Only approved study staff, including the Principle 
Investigator, Study Physician/PA, and Clinical Research Specialist are permitted to make entries, changes, or 
corrections in the CRF. For paper CRFs, errors will be crossed out with a single line, and this line will not obscure the 
original entry.  Changes or corrections will be dated, initialed, and explained (if necessary). The Principal Investigator 
or authorized key personnel will maintain a record of the changes and corrections. For electronic CRFs, an audit trail 
will be maintained by the electronic CRF management system (REDCap). 
14.5. PRIVACY, CONFIDENTIALITY, AND DATA STORAGE 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be maintained.  
Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based Research group. 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of the 
study.  Prospective participants will be consented in an exam room where it is just the research staff, the patient and 
his family, if desired. For all future visits, interactions with research staff (study doctor and study coordinators) 
regarding research activities will take place in a private exam room. All research related interactions with the 
participant will be conducted by qualified research staff who are directly involved in the conduct of the research 
study. 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key accessible 
only by the research staff. Subjects will be identified only by a unique study number and subject initials. Electronic 
records of subject data will be maintained using a dedicated database, REDCap, which is housed in an encrypted and 
password-protected Duke Server behind a firewall. Access to electronic databases will be limited to key personnel. 
Subject data may be stored temporarily on encrypted and password-protected portable memory devices such as 
flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory devices 
will be de-identified. Subject data will be deleted from the portable memory device at the earliest opportunity. The 
security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.   
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
14.6. DATA AND SAFETY MONITORING 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan. For a 
more detailed description of the DSMP for this protocol, refer to Section 11 (Sections 11.7 and 11.8 in particular) 
along with section 12. 
14.7. PROTOCOL AMENDMENTS 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB and submitted to 
the IND prior to implementation.  IRB approval is not required for protocol changes that occur to protect the safety 
of a subject from an immediate hazard.  However, the Principal Investigator must inform the IRB, FDA, and all other 
applicable regulatory agencies of such action immediately. 
14.8. RECORDS RETENTION 
The Principal Investigator will maintain study-related records for at least six years after study completion.  


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15. APPENDICES 
 
APPENDIX 1: Exclusionary Medication 
The following medications are considered exclusionary if currently or recently being taken by a participant: 
Abilify (aripiprazole)  
Abiraterone Acetate 
Adderall (dextro- & 
amphetamine)  
Alosetron 
Amantadine 
Amitriptyline (Elavil, Endep) 
Amoxapine (Asendin)  
Anafranil (clomipramine)  
Aripiprazole (Abilify)  
Asenapine (Saphris)  
Asendin (amoxapine) 
Asunaprevir 
Atomoxetine (Strattera) 
Aventyl (nortriptyline) 
Belviq (Lorcaserin) 
Bontril (phendimetrazine)  
Brexpiprazole (Rexulti)  
Bromocriptine 
Buproprion (Wellbutrin, 
Zyban) 
Bystolic (Nebivolol) 
Cabergoline 
Carbamazepine (Tegretol)  
Celexa (citalopram)  
Chantix (Varenicline) 
Cinacalcet 
Citalopram (Celexa)  
Clomipramine (Anafranil)  
Clonidine 
Clopidogrel (Plavix) 
Clopress  
Clozapine (Clozaril) 
Cobicistat 
Concerta (methylphenidate) 
ConZip (Tramadol)  
Coumadin (warfarin)  
Dapoxetine (Priligy)  
Darifenacin 
Darunavir 
Daytrana (methylphenidate) 
DEP (Tenuate) 
Desipramine (norpramin)  
Desvenlafaxine 
Desyrel (trazodone)  
Detrol (Tolterodine)  
Dexedrine 
(dextroamphetamine) 
Dexmethylphenidate 
(Focallin) 
Dextroamphetamine  
Digoxin  
Dolasetron 
DOPamine  
Dosulepin 
Doxepin (Sinequan)  
Duloxetine 
Efavirenz (Sustiva)  
Effexor (venlafaxine) 
Elavil (amitriptyline) 
Eldepryl (Selegiline)  
Endep (amitriptyline) 
Ergonovine 
Ergotamine 
Escitalopram 
Fluoxetine (Prozac, Sarafem)  
Fluphenazine (Prolixin)  
Fluvoxamine (Luvox) 
Focalin 
(dexmethylphenidate)  
Geodon (ziprasidone) 
Granisetron 
Heparin  
Imatinib 
Imipramine (Tofranil, 
Tipramine, Norfranil)  
Invega (paliperidone) 
Isocarboxazid (Marplan)  
Kaletra (Lopinavir)  
Keppra (Levetiracetam)  
Lacosamide (Vimpat)  
Lamictal (lamotrigine)  
Lamotrigine (Lamictal) 
Latuda (lurasidone)  
Levetiracetam (Keppra)  
Levomethadyl 
Levomilnacipran 
Linezolid  
Lisdexamfetamine(Vyvanase)  
Lithium  
Lofepramine 
Lopinavir (Kalentra) 
Lopressor (Metoprolol)  
Lorcaserin (Belviq)  
Lovenox  
Ludiomil (Maprotiline)  
Lumefantrine 
Lurasidone (Latuda)  
Luvox (fluvoxamine) 
Maprotiline (Ludiomil)  
Marplan (isocarboxazid)  
Mellaril (Thiorizadine)  
Metadate (methylphenidate) 
Methylene Blue 
Methylergonovine 
Methylin (methylphenidate)  
Methylphenidate (Ritalin, 
Concerta, Metadate, 
Daytrana, Methylin) 
Metoclopramide (Reglan) 
Metoprolol (Lopressor)  


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AXS-05 on Smoking Behavior 
56 
Midamor (AMILoride) 
MiFEPRIStone (Mifeprex)  
Mirabegron 
Mirapex (pramiprexole)  
Mirtazapine (Remeron) 
Moclobemide 
Namenda (Memantine)  
Nardil (phenelzine)  
Nebivolol (Bystolic)  
Nefazadone (Serzone) 
Nevirapine (Viramune)  
Nilotinib 
Norfranil (imipramine)  
Norpramin (desipramine)  
Nortriptyline (Aventyl, 
Pamelor)  
Norvir (Ritonavir)  
Olanzapine (Zyprexa)  
Ondansetron 
Oxaliplatin  
Paliperidone (Invega)  
Palonosestron 
Pamelor (nortriptyline)  
Panobinostat 
Parecoxib 
Parnate (tranylcypromine)  
Paroxetine (Paxil) 
Peginterferon Alfa-2B 
Pergolide 
Perhexiline  
Phendimetrazine (Bontril)  
Phenelzine (Nardil) 
Phentermine 
Pindolol 
Plavix (clopidogrel) 
Pramiprexole (Mirapex)  
Priligy (dapoxetine) 
Procainamide (Procanbid, 
Pronestyl)  
Procarbazine 
Prolixin (fluphenazine)  
Promethazine 
Propafenone (Rhythmol) 
Protriptyline (Vivactil) 
Qsymia (Phentermine + 
Topiramate) 
Quetiapine  
Quinidine 
Quininet 
Ramosetron 
Rasagiline 
Remeron (mirtazapine) 
Rexulti (Brexpiprazole)  
Rifampin (Rifadin)  
Risperdal (risperidone)  
Risperidone (Risperdal) 
Ritalin (Methylphenidate) 
Ritonavir (Norvir)  
Rofecoxib (Vioxx) 
Rolapitant 
Ropinirole (Requip) 
Rythmol SR  
Safinamide 
SAMe (S-
adenosylmethionine) 
Saphris (asenapine)  
Sarafem (fluoxetine)  
Selegiline  
Seroquel 
Sertraline 
Sinequan (doxepin) 
Soltamox (tamoxifen)  
St John’s Wort 
Strattera (atomoxetine)  
Surmontil (trimipramine) 
Sustiva (Efavirenz) 
Symbax (Fluoxetine / 
Olanzapine) 
Symmetrel (amantadine)  
Tamoxifen (soltamox)  
Tasigna  
Tedizolid 
Tegretol (Carbamazepine)  
Tenuate (DEP)  
Tepadina  
Terbinafine 
Thioridazine  
Thiotepa  
Tipramine (imipramine) 
Tipranavir 
Tofranil (imipramine)  
Tolterodine (Detrol)  
Tranylcypromine (Parnate) 
Trazodone (Desryl) 
Trimipramine (Surmontil) 
Tropisetron 
Venlafaxine (Effexor)  
Vilazodone (Viibryd) 
Vimpat (lacosamide) 
Viramune (Nevirapine)  
Visken (pindolol)  
Vivactil (protriptyline)  
Vortioxetine (Trintellix)  
Vyvanase (lisdexamfetamine)  
Warfarin (Coumadin)  
Wellbutrin (bupropion) 
Zelapar  
Ziprasidone (Geodon) 
Zyban (bupropion) 
Zyprexa (olanzapine)  
 
 
 


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AXS-05 on Smoking Behavior 
57 
 
The following medications  will require the study clinician  discretion to determine if they are exclusionary: 
Acetaminophen (Tylenol) 
Actiq® 
Adenocard (Adenosine)  
Alfenta®  
Alfentanil 
Almotriptan (Axert)  
Alprazolam (Xanax) 
Ambien (zolpidem) 
Amerge (Naratriptan) 
AMILoride  
Amrix (Cyclobenzaprine) 
Anexsia®  
Aquachloral (chloral hydrate) 
Ascomp® w/Codeine  
Aspirin (ASA) 
Astramorph™ PF 
Ativan (lorazepam) 
Avelox (Moxifloxacin) 
Avinza®  
Axert (Almotriptan)  
Axid (Nizatidine) 
B and O Supprettes®  
Baclofen (Lioresal) 
Balacet 325™  
Bancap HC® 
Baxdela (Delafloxicin)  
Belladonna; Opium 
Buprenomorphine  
Buspar (buspirone) 
Buspirone (Buspar) 
Capital® with Codeine  
Carisoprodol (Soma) 
Celecoxib (Celebrex) 
Ceta-Plus™ 
Cetraxal (Cipro)  
Chloral Hydrate 
(Aquachloral,Somnote) 
Chlordiazepoxide HCl 
(Librium) 
Chlorzoxazone (Parafon 
Forte, Relax-DS) 
Cimetidine  
Ciprofloxacin (Cetraxal)  
Clonazepam (Klonopin) 
Codeine 
Co-Gesic®  
Combunox™ 
ComfortPak™ 
Cyclobenzaprine (Flexeril) 
Dalmane (Flurazepam) 
Damason-P® 
Dantium (Dantrolene) 
Dantrolene (Dantrium) 
Darvocet 
Darvon® 
Delafloxicin (Baxdela)  
Demerol® 
DepoDur® 
Diamorphine  
Diazepam (Valium) 
Dihydroergotamine 
Dilaudid®  
Dilaudid-HP® 
Diphenoxylate  
Dirame® 
Diskets® 
Ditropan (oxybutynin) 
Dolagesic™ 
Dolophine® 
Dolorex™ Forte 
Duocet™ 
Duragesic®  
Duramorph® 
Eletriptan (Relpax) 
Eloxatin (Oxaliplatin)  
Endocet® 
Endocodone® 
Endodan® 
Estazolam (ProSom) 
Eszopiclone (Lunesta) 
Eth-OxyDose™  
Factive (Gemifloxacin)  
Famotidine (Pepcid)  
Fentanyl 
Fentora™ 
Fioricet® with Codeine  
Fiorinal® with Codeine  
Fiortal® with Codeine  
Flexeril (Cyclobenzaprine) 
Floxin (Ofloxacin) 
Flurazepam (Dalmane) 
Frova (Frovatriptan)  
Gabapentin (Neurontin, 
Horizant)  
Gemifloxacin (Factive)  
Glucophage (Metformin) 
Halcion (triazolam) 
Horizant (gabapentin)  
Hycet™ 
Hycodan® 
Hydrocet®  
Hydrocodone  
Hydrocodone; Ibuprofen  
Hydrogesic™  
Hydromet®  
Hydromorphone  
Hydropane®  
Ibuprofen (Motrin, Advil) 
Imitrex (Sumatriptan) 
Infumorph®  
Kadian® 
Kava 
Klonopin (clonazepam) 
Levaquin  
Levo-Dromoran®  
Levo-Dromoran™  
Levofloxacin  


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58 
Levorphanol 
Librium (chlordiazepoxide 
HCl) 
Lomefloxacin  
Lorazepam (Ativan) 
Lorcet®  
Lorcet® Plus  
Lorcet®-HD 
Lortab ASA®  
Lortab®  
Lunesta (eszopiclone) 
Lyrica (pregabalin)  
Margesic-H™ 
Maxalt (Rizatriptan) 
Maxidone™ 
Memantine (Namenda)  
Meperidine 
Meperidine;  
Meperitab™ 
Metaxolone (Skelaxin) 
Metformin (Glucophage) 
Methadone  
Methadose®  
Methocarbamol (Robaxin) 
Milnacipran (Savella)  
MorphiDex™  
Morphine  
Motofen®  
Moxifloxacin (Avelox)  
MS Contin® 
MSIR®  
Nalidixic Acid (NegGram)  
Naltrexone 
Naproxen, Napropsyn (Aleve) 
Naratriptan (Amerge) 
Narvox  
NegGram (Nalidixic Acid)  
Neurontin (gabapentin)  
Nizatidine (Axid) 
Norflex (Orphenadrine) 
Norfloxacin  
Noroxin  
Nucynta (tapentadol) 
Numorphan® 
Ofloxacin  
Opana® 
Opana® ER 
Opium Tincture 
Oramorph® 
Oramorph® SR 
Orlaam® 
Orphenadrine (Norflex) 
Oxybutynin (Ditropan)  
Oxycodone 
Oxycodone; Naltrexone  
OxyContin® 
OxyFast®  
OxyIR® 
Oxymorphone  
Oxytrex™ 
Palladone™ 
Panlor® DC 
Panlor® SS 
Paregoric, Camphorated 
Opium 
Passionflower 
Pepcid (Famotidine) 
Percocet® 
Percodan® 
Percodan-Demi® 
Percolone® 
Perloxx 
Phenco-Care™ 
Phrenilin® w/ Caffeine, 
Codeine 
Pipemidic Acid 
PP-Cap™ 
Pregabalin (Lyrica)  
Propacet® 
Propiram 
Propoxyphene 
ProSom (estazolam) 
Prozac (fluoxetine) 
Pyregesic-C™ 
Ralivia 
Ranitidine 
Relacore (contains 
passionflower) 
Relafen 
Remifentanil  
Reprexain™  
Requip (Ropinirole) 
Restoril 
Rizatriptan (Maxalt)  
Robaxin (Methocarbamol) 
Roxanol™ 
Roxicet®  
Roxicodone®  
Savella (milnacipran) 
Skelaxin (Metaxalone) 
Soma (Carisoprodol) 
Soma® Compound w/ 
Codeine 
Somnote (chloral hydrate) 
Sparfloxacin 
Stagesic®  
Sublimaze® 
Suboxone  
Subutex 
Sufenta® 
Sufentanil  
Sumatriptan (Imitrex)  
Synalgos® DC  
Tagamet HB  
Tapentadol (Nucynta) 
Temazepam 
Tizanidine (Zanaflex) 
Topamax (Topiramate)  
Topiramate (Topamax)  
Tramadol 
Triazolam (Halcion) 
Tylagesic™  
Tylenol® with Codeine  
Tylox® 
TY-PAP with Codeine  
Ultiva® 


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AXS-05 on Smoking Behavior 
59 
Ultracet 
Ultram  
Valerian  
Valium (diazepam) 
Vicodin®  
Vicoprofen®  
Vopac™ 
Xanax (alprazolam) 
Xodol 
Xodol 10/300 
Zagam (sparfloxacin)  
Zanaflex (tizanidine) 
Zantac  
Zerlor  
Zolpidem (Ambien) 
Zomig (Zolmatriptan) 
Zydone® 
 
 
 


60 
 
APPENDIX 2: Medical History 
Major Medical Conditions: 
Have you had any of the following conditions?  
 Yes   No      High blood pressure (Hypertension) 
 
 Yes   No      Heart attack OR heart disease diagnosis by coronary angiogram 
 
 Yes   No      Problems with heart valves such as regurgitation, stenosis, or artificial valve 
 
 Yes   No      Heart rhythm problem such as atrial fibrillation, tachycardia, or pacemaker 
 
 Yes   No      Heart failure requiring a diuretic (water pill) 
 
 Yes   No      Skin problems requiring medication 
 
 Yes   No      Liver cirrhosis (with jaundice or swollen abdomen) 
 
 Yes   No      Liver problems other than cirrhosis (e.g. hepatitis, fatty liver) 
 
 Yes   No      Kidney failure requiring dialysis 
 
 Yes   No      Chronic Kidney Disease not requiring dialysis 
 
 Yes   No      Chronic diarrhea due to Irritable Bowel Syndrome, Crohn's Disease, Inflammatory Bowel 
 
 Yes   No      Stomach/ Duodenal Ulcer (Gastrointestinal Ulcer) 
 
 Yes   No      Chronic Bronchitis (cough every morning) 
 
 Yes   No      Chronic Obstructive Pulmonary Disease (COPD) (Emphysema) 
 
 Yes   No      Asthma 
 
 Yes   No      Other chronic lung disorder such as Tuberculosis, Pulmonary Fibrosis, Sarcoid, or other 
 
 Yes   No      Stroke/ TIA (mini-stroke) 
 
 Yes   No      Seizure disorder 
 
 Yes   No      Regular headaches 
 
 Yes   No      Unexplained fainting spells 
 
 Yes   No      Insomnia requiring medications 
 
 Yes   No      Other neurologic conditions 
 
 Yes   No      Problems giving blood samples 
 
 Yes   No      Anemia requiring iron 
 
 Yes   No      Blood disorder 
 
 Yes   No      Rheumatic Disease such as Rheumatoid Arthritis, Fibromyalgia, or other 
 
 Yes   No      Sinusitis/ Seasonal allergies 
 
 Yes   No      Diabetes requiring insulin or other medications 
 
 Yes   No      Thyroid disease/ condition 
 


61 
 
 Yes   No      Cancer 
 
 Yes   No      Depression/ Anxiety/ Bipolar disorder 
 
 Yes   No      Suicidal ideation (thinking about ways to commit suicide) within the past year 
 
 Yes   No      Suicide attempt during your lifetime 
 
 Yes   No      Schizophrenia 
 
 Yes   No      Post-Traumatic Stress Disorder (PTSD) 
____ 
 Yes   No      Other Psychiatric problems (Borderline, Schizoaffective, Hypomania, ADHD) 
 
 Yes   No      Chronic infections syndrome such as HIV, CMV, Epstein Barr 
Please list any hospitalizations in the past 10 years.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Please list any serious injuries or accidents.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Please list any surgeries or major procedures.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Women Only: 
Date of last menstrual cycle:  __________________ 
Are you menstruating regularly?       Yes       No 
Are you post menopausal (natural or from surgery)?       Yes       No 
Are you willing to use medically acceptable contraceptive measures for the duration of the study?  
 
Acceptable methods of contraception include (1) surgical sterilization (such as tubal ligation or hysterectomy, 
(2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier 
methods (such as condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). 
Contraceptive measures such as rhythm method or Plan B™, sold for emergency use after unprotected sex, are 
not acceptable methods for routine use. 
  Yes       No 
 
 


62 
 
Family History 
Has any first degree family member (child, parent, or sibling) had any of the following illnesses? 
Illness 
Which family member? 
Anemia or Blood Disease 
 
Cancer 
 
Diabetes 
 
Heart Disease 
 
High Blood Pressure 
 
Severe Mental Illness 
 
Stroke 
 
Substance abuse (alcohol, tobacco, or other) 
 
Other serious illness 
 
 
Social History 
Do you drink alcohol (e.g. beer, wine, liquor)?    yes     no    
If YES, how many days per week do you have a drink containing alcohol? _________ 
How many drinks do you have on your heaviest drinking day of the week? _________ 
Do you currently drink coffee and / or tea?    yes     no 
If YES, how many cups per day? __________ 
Have you used a non-prescription drug such as marijuana, cocaine or heroin in the last month?    yes     no 
If YES, what drug / substance? ____________________________________________ 
General Health 
Do you use oxygen?     
 no     yes, continuously     yes, for exertion or sleep 
Can you walk up 2 flights of stairs? 
 no     yes, without stopping     yes, but I would need to stop along the way.                 
How well do you walk? 
 I walk independently     I walk with a cane     I walk with a walker     I use a wheelchair 
Have you ever experienced a seizure or seizure-like activity? 
 Yes 
No 


63 
 
Medications 
Please list any medications you are allergic to: 
1. 
2. 
3. 
  
Please list all medications you are now taking or have used in the last month (include over-the-counter drugs, vitamins, and 
especially prescriptions). Ok to skip dates for long term medications:  
Name of Medication 
Dosage 
Start Date 
Stop Date 
Prescribed for what problem? 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
6. 
 
 
 
 
7. 
 
 
 
 
8.  
 
 
 
 
 
Have you used experimental or investigational drugs in the past 30 days?    Yes    No    
 
Smoking Cessation Medications    
For each of the following, mark if you have used the medication, experienced any side effects, allergy or intolerance with usage, 
or had to stop taking the medication due to side effects: 
 
 
Not 
used 
Used 
Side Effects 
Stopped due to Side 
Effects? 
Yes 
No 
Nicotine Patch 
 
 
 
 
 
Nicotine Gum 
 
 
 
 
 
Nicotine Lozenge 
 
 
 
 
 
Nicotine Inhaler 
 
 
 
 
 
Zyban 
(Wellbutrin, 
Bupropion) 
 
 
 
 
 
Chantix (Varenicline) 
 
 
 
 
 
 
Have you used any of these medications in the past 30 days?    Yes    No 
 


64 
 
APPENDIX 3: Patient Health Questionnaire-989 
Over the past two weeks, how often have you been bothered by any of the following problems? 
 
Not at all 
Several 
days 
More than 
half 
the 
days 
Nearly 
every day 
1. Little interest or pleasure in doing 
things 
0 
1 
2 
3 
2. Feeling 
down, 
depressed 
or 
hopeless 
0 
1 
2 
3 
3. Trouble falling or staying asleep, 
or sleeping too much 
0 
1 
2 
3 
4. Feeling tired or having little 
energy 
0 
1 
2 
3 
5. Poor appetite or overeating 
 
0 
1 
2 
3 
6. Feeling bad about yourself — or 
that you are a failure or have let 
yourself or your family down 
0 
1 
2 
3 
7. Trouble concentrating on things, 
such as reading the newspaper or 
watching television 
0 
1 
2 
3 
8. Moving or speaking so slowly that 
other people could have noticed? 
Or the opposite — being so fidgety 
or restless that you have been 
moving around a lot more than 
usual 
0 
1 
2 
3 
9. Thoughts that you would be better 
off dead or hurting yourself in some 
way 
0 
1 
2 
3 
 
Scoring 
Depression Severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe.  
 
 
 


65 
 
APPENDIX 4: Generalized Anxiety Disorder 7-item Scale (GAD-7)76 
 
Over the last 2 weeks, how often have you been bothered by any of 
the following problems?  
Not at all 
Several 
days 
More than 
half 
the 
days 
Nearly every 
 day 
1. 
Feeling nervous, anxious or on edge 
0 
1 
2 
3 
2. 
Not being able to stop or control worrying 
0 
1 
2 
3 
3. 
Worrying too much about different things 
0 
1 
2 
3 
4. 
Trouble relaxing 
0 
1 
2 
3 
5. 
Being so restless that it is hard to sit still 
0 
1 
2 
3 
6. 
Becoming easily annoyed or irritable 
0 
1 
2 
3 
7. 
Feeling afraid as if something awful might happen 
0 
1 
2 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate:  Add scores of GAD-7 Responses together for total  
0-5 = mild anxiety 
6-10 = moderate anxiety 
11 or above = high anxiety 
  


66 
 
APPENDIX 5: Smoking History Questionnaire 
Please answer the following questions are about your history of smoking, use of other products and 
medications.   
 
1. How many cigarettes have you smoked per day on average for most of your life?  
          ________ [1-99]  
2. How many years have you smoked? ________ [1-99] 
 
 
3. Do you usually smoke menthol or non-menthol cigarettes?  
1 = Non-Menthol 
2 = Menthol 
3 = Both 
0 = Don’t know  
 
4. Does your spouse/partner smoke?  
 
1 = YES 
 
2 = NO 
 
3 = Do not have a spouse/partner 
 
0 = Don’t know  
 
5. If you decided to quit, how likely would the people close to you support your decision to quit? 
1 = Not likely at all 
2 = Very unlikely 
3 = Somewhat unlikely 
4 = Neither likely nor unlikely 
5 = Somewhat likely 
6 = Very likely 
7 = Extremely likely  
0 = Don’t know   
 
6. How many times in your life have you stopped smoking for one day or longer because you were trying 
to quit smoking?  _______ [0-99]  
 
 
7. Have you used the following tobacco products in the last week? (Select all that apply) 
 
1 = Cigarettes 
 
2 = Cigars 
 
3 = Pipes 
Calculate:  number of cigs/day for most of your life (Q1)/20 x years smoked (Q2) – this will yield: 
“Pack Years” to be generated as an automatic input into the Specialist H+P.   
 (Q1 is /20 because there are 20 cigs in a pack)  


67 
 
 
4 = Hookah 
 
5 = Cigarillos 
 
6 = E-cigarettes 
 
7 = Chewing tobacco 
 
8 = Orbs/sticks/sheets 
 
9 = Snuff 
 
10 = Other 
 
8. During the last week did you use any of the following drugs? (Select all that apply)  
 
 
0 = None 
 
1 = Marijuana 
 
2 = Cocaine/Crack 
 
3 = Meth 
 
4 = PCP 
 
5 = Heroin 
 
6 = Other 
 
9. During the last week, did you use an opiate such as Codeine, Morphine, MS Contin, OxyContin, 
Oxycodone, Percocet, Hydrocodone, Vicodin, Hydromophone, Dilaudid, Duragesic or Fentanyl?   
 
1 = Yes 
2 = No 
0 = Don’t know  
 
10. During the last week, did you use a benzodiazepine such as Lorazapam, Ativan, Valium, Alprazolam, 
Xanax, Clonazepam or Klonopin?  
1 = Yes 
2 = No 
0 = Don’t know 
 
 
 
 
 
 
 
 
 


68 
 
APPENDIX 6: Fagerström Test of Nicotine Dependence64 
1. How soon after you wake up do you smoke your first cigarette? 
 
3= Within 5 minutes  
   
 
2= 6-30 minutes  
   
 
1=31-60 minutes  
  
 
0= More than 60 min  
 
 
 
 
 
 
2. Do you find it difficult to refrain from smoking in places where it is forbidden, (e.g. in church, at the library, in the cinema)?  
    
0 = No 
 
   
    
1 = Yes 
 
 
 
 
 
3. Which cigarette would hate most to give up? 
   
1 = The first one in the morning 
   
0 = All others  
   
 
 
  
4. How many cigarettes per day do you smoke? 
   
0= 10 or less  
  
   
1= 11-20   
  
   
2= 21-30   
  
   
3= 31 or more  
  
 
 
 
 
5. Do you smoke more frequently during the first hours after waking than the rest of the day? 
    
0 = No 
 
  
    
1 = Yes 
 
  
 
 
 
6.  Do you smoke when you are so ill that you are in bed most of the day? 
    
0 = No 
 
  
    
1 = Yes 
 
  
 
 
  
  
 
 
 
 
 
 
 
Calculate:  Add scores of all 6 items.   
 
1-2 = low dependence 
3-4 = low-moderate dependence 
5-7 = moderate dependence 
8+ = high dependence 


69 
 
APPENDIX 7: Recent Smoking Questionnaire 
The follow questions are about your recent smoking 
1. In the last 30 days, have you smoked at all - even a puff?  
1=YES 
2 =NO 
0 = Don’t know  
2. In the last 7 days, have you smoked at all - even a puff?    
1=YES 
2 = No 
0 = Don’t know  
3.  In the last 7 days, how many days did you smoke cigarettes?  
____   [0-7]   
  
4. In the last 7 days, how many cigarettes have you smoked per day?  
 
_____ [0-99]  
 
 
 


70 
 
APPENDIX 8: Screening Week Diary 
 
Date 
Record the 
number of 
cigarettes that 
you smoked 
each day. 
 
Baseline 
Visit 
Office Use Only 
 
Date 
Record the 
number of 
cigarettes that 
you smoked 
each day. 
 
Baseline 
Visit 
Office Use Only 
____/____ 
D1 
______ 
# of cigs 
 
o 
 
____/____ 
D8 
______ 
# of cigs 
 
o 
____/____ 
D2 
______ 
# of cigs 
 
o 
 
____/____ 
D9 
______ 
# of cigs 
 
o 
 
____/____ 
D3 
______ 
# of cigs 
 
o 
 
____/____ 
D10 
______ 
# of cigs 
 
o 
____/____ 
D4 
______ 
# of cigs 
 
o 
 
____/____ 
D11 
______ 
# of cigs 
 
o 
____/____ 
D5 
______ 
# of cigs 
 
o 
 
____/____ 
D12 
______ 
# of cigs 
 
o 
____/____ 
D6 
______ 
# of cigs 
 
o 
 
____/____ 
D13 
______ 
# of cigs 
 
o 
____/____ 
D7 
______ 
# of cigs 
 
o 
 
____/____ 
D14 
______ 
# of cigs 
 
o 
 
 


71 
 
APPENDIX 9: Smoking, Medication Use, Urges and Mood & Diary 


72 
 


73 
 


74 
 


75 
 
 


76 
 
 
APPENDIX 10: Medication Side Effects Questionnaire 
 
 
 


77 
 
APPENDIX 11: Mood and Physical Symptoms Scale-268 
The next questions are about how you have been feeling over the past 24 hours.  
1.  How much of the time have you felt the urge to smoke in the past 24 hours?   
0=Not at all 
1=A little of the time 
2=A lot of the time 
3=Almost all of the time 
4= All of the time 
2.  How strong have the urges been?  
     0=No urge 
     1=Slight  
     2=Moderate  
     3=Strong 
     4=Very Strong  
     5=Extremely Strong  
 
 
 
 
Calculate:  Please add scores of questions above   
 
0-2 = Mild 
3-6 = Moderate 
7-10 = Severe  


78 
 
APPENDIX 12: State-Trait Anxiety Inventory70 
A number of statements which people have used to describe themselves are given below. Read each statement and then circle 
the appropriate number to the right of the statement to indicate how you feel right now, that is at this moment. There are no 
right or wrong answers. Do not spend too much time on any one statement but give the answer which seems to describe your 
present feelings best. 
 
Not at all 
Somewhat 
Moderately So 
Very Much So 
1. I feel calm 
1 
2 
3 
4 
2. I feel secure  
1 
2 
3 
4 
3. I am tense 
1 
2 
3 
4 
4. I feel strained 
1 
2 
3 
4 
5. I feel at ease 
1 
2 
3 
4 
6. I feel upset 
1 
2 
3 
4 
7. I am presently worrying over possible 
misfortunes 
1 
2 
3 
4 
8. I feel satisfied 
1 
2 
3 
4 
9. I feel frightened 
1 
2 
3 
4 
10. I feel comfortable 
1 
2 
3 
4 
11. I feel self-confident 
1 
2 
3 
4 
12. I feel nervous 
1 
2 
3 
4 
13. I am jittery 
1 
2 
3 
4 
14. I feel indecisive 
1 
2 
3 
4 
15. I am relaxed 
1 
2 
3 
4 
16. I feel content 
1 
2 
3 
4 
17. I am worried 
1 
2 
3 
4 
18. I feel confused 
1 
2 
3 
4 
19. I feel steady 
1 
2 
3 
4 
20.  I feel pleasant 
1 
2 
3 
4 
 
 
 
 
 


79 
 
A number of statements which people have used to describe themselves are given below. Read each statement and then circle 
the appropriate number to the right of the statement to indicate how you generally feel. There are no right or wrong answers. 
Do not spend too much time on any one statement but give the answer which seems to describe you generally feel. 
 
 
Almost 
Never 
Sometimes 
Often 
Almost Always 
21. I feel pleasant 
1 
2 
3 
4 
22. I feel nervous and restless  
1 
2 
3 
4 
23. I feel satisfied with myself 
1 
2 
3 
4 
24. I wish I could be as happy as others seem to be 
1 
2 
3 
4 
25. I feel like a failure 
1 
2 
3 
4 
26. I feel rested 
1 
2 
3 
4 
27. I am “calm, cool, and collected” 
1 
2 
3 
4 
28. I feel that difficulties are piling up so that I cannot 
overcome them 
1 
2 
3 
4 
29. I worry too much over something that doesn’t 
really matter 
1 
2 
3 
4 
30. I am happy 
1 
2 
3 
4 
31. I have  disturbing thoughts 
1 
2 
3 
4 
32. I lack self confidence 
1 
2 
3 
4 
33. I feel secure 
1 
2 
3 
4 
34. I make decisions easily 
1 
2 
3 
4 
35. I feel inadequate 
1 
2 
3 
4 
36. I am content 
1 
2 
3 
4 
37. Some unimportant thought runs through my 
mind and bothers me 
1 
2 
3 
4 
38. I take disappointments so keenly that I can’t put 
them out of my mind 
1 
2 
3 
4 
39. I am a steady person 
1 
2 
3 
4 
40.  I get in a state of tension or turmoil as I think 
over my recent concerns and interests 
1 
2 
3 
4 
Scoring: The total score ranges from 0–63. The following guidelines are recommended for the interpretation of scores: 0–9, 
normal or no anxiety; 10–18, mild to moderate anxiety; 19–29, moderate to severe anxiety; and 30–63, severe anxiety. 
 
 


80 
 
APPENDIX 13: Center for Epidemiologic Studies Depression Scale-R 
Below is a list of the ways you might have felt or behaved. Please tell me how often you have felt this way during the past week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not at all or 
Less than 1 
day 
1-2 days 
3-4  days 
5-7 days 
Nearly 
every 
day for 2 weeks 
1. My appetite was poor 
 
 
 
 
 
2. I could not shake off the blues. 
 
 
 
 
 
3. I had trouble keeping my mind 
on what I was doing. 
 
 
 
 
 
4. I felt depressed 
 
 
 
 
 
5. My sleep was restless  
 
 
 
 
 


81 
 
6. I felt sad  
 
 
 
 
 
7.I could not get going 
 
 
 
 
 
8. Nothing made me happy  
 
 
 
 
 
9. I felt like a bad person  
 
 
 
 
 
10. I lost interest in my usual 
activities  
 
 
 
 
 
11. I slept much more than usual  
 
 
 
 
 
12. I felt like I was moving too 
slowly  
 
 
 
 
 
13. I felt fidgety  
 
 
 
 
 
14. I wished I were dead  
 
 
 
 
 
15. I wanted to hurt myself  
 
 
 
 
 
16. I was tired all the time  
 
 
 
 
 
17. I did not like myself  
 
 
 
 
 
18. I lost a lot of weight without 
trying to 
 
 
 
 
 
19. I had a lot of trouble getting to 
sleep  
 
 
 
 
 
20. I could not focus on the 
important things. 
 
 
 
 
 
 
 


82 
 
APPENDIX 14: Minnesota Nicotine Withdrawal Scale (MNWS)69 
Behavior Rating Scale 
Self-Report 
Please rate yourself for the period for the last 24 hours. 
DSM – 5 Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
1. Angry, irritable, frustrated 
0 
1 
2 
3 
4 
2. Anxious, nervous 
0 
1 
2 
3 
4 
3. Depressed mood, sad 
0 
1 
2 
3 
4 
4. Difficulty concentrating 
0 
1 
2 
3 
4 
5. Increased appetite, hungry, weight gain 
0 
1 
2 
3 
4 
6. Insomnia, sleep problems, awakening at night 
0 
1 
2 
3 
4 
7. Restlessness 
0 
1 
2 
3 
4 
Other Validated Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
8. Desire or craving to smoke 
0 
1 
2 
3 
4 
Other Possible Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
9. Constipation 
0 
1 
2 
3 
4 
10. Coughing 
0 
1 
2 
3 
4 
11. Decreased pleasure from events 
0 
1 
2 
3 
4 
12. Dizziness 
0 
1 
2 
3 
4 
13. Drowsy 
0 
1 
2 
3 
4 
14. Impatient 
0 
1 
2 
3 
4 
15. Impulsive 
0 
1 
2 
3 
4 
 
TOTAL Score Questions 1-15: _____ 
 
 
 
 
 
 
 
 


83 
 
APPENDIX 15: Pittsburgh Sleep Quality Index (PSQI)77 
The following questions relate to your usual sleep habits during the past week only. Your answers should indicate the most 
accurate reply for the majority of days and nights in the past week. Please answer all questions. 
 
1. During the past week, what time have you usually gone 
to bed at night? 
________ Bed time 
2. During the past week, how long (in minutes) has it 
usually taken you to fall asleep each night? 
                  ________ Number of minutes 
3. During the past week, what time have you usually gotten 
up in the morning? 
           ________ Getting up time 
4. During the past week, how many hours of actual sleep 
did you get at night? (This may be different than the 
number of hours you spent in bed.) 
                         ________ Hours of sleep per night 
For each of the remaining questions, check the one best response. Please answer all questions. 
 
5. During the past week, how often have you had trouble sleeping because you… 
 
 
Not during the 
past week 
Once in the past 
week 
Twice in the last 
week 
Three or more 
times in the last 
week 
a. Cannot get to sleep within 30     
    minutes 
0 
1 
2 
3 
b. Wake up in the middle of the night   
     or early morning 
0 
1 
2 
3 
c. Have to get up to use the  
    bathroom 
0 
1 
2 
3 
d. Cannot breathe comfortably 
0 
1 
2 
3 
e. Cough or snore loudly  
0 
1 
2 
3 
f. Feel too cold 
0 
1 
2 
3 
g. Feel too hot 
0 
1 
2 
3 
h. Had bad dreams 
0 
1 
2 
3 
i. Have pain 
0 
1 
2 
3 
j. Other reasons (please describe) 
0 
1 
2 
3 
 
 
 
 
 
 


84 
 
 
Not during 
the 
past 
week 
Once in the 
past week 
Twice 
in 
the 
last 
week 
Three 
or 
more times 
in the last 
week 
6. During the past week, how often have you taken 
medicine to help you sleep (prescribed or over-the 
counter)? 
0 
1 
2 
3 
7. During the past week, how often have you had trouble 
staying awake while driving, eating meals, or 
engaging in social activity? 
0 
1 
2 
3 
 
8. During the past week, how much of a problem has it been for you to keep up enough enthusiasm to get things  
    done? 
a. 0 - No problem at all 
b. 1 - Only a very slight problem 
c. 
2 - Somewhat of a problem 
d. 3 - A very big problem 
9. During the past week, how would you rate your sleep quality overall? 
a. 0 - Very good 
b. 1 - Fairly good 
c. 2 - Fairly bad 
d. 3 - Very bad 
10. Do you have a bed partner or roommate? 
a. 0 - No bed partner or roommate 
b. 1 - Partner/roommate in other room 
c. 
2 - Partner in same room, but not same bed 
d. 3 - Partner in same bed 
If you have a roommate or bed partner, ask him/her how often in the past week you have had… 
 
Not during 
the 
past 
week 
Once in the 
past week 
Twice 
in 
the 
last 
week 
Three 
or 
more times 
in the last 
week 
a. Loud snoring 
0 
1 
2 
3 
b. Long pauses between breaths while asleep 
0 
1 
2 
3 
c. Legs twitching or jerking while you sleep 
0 
1 
2 
3 
d. Episodes of disorientation or confusion during sleep 
0 
1 
2 
3 
e. Other restlessness while you sleep (please describe) 
0 
1 
2 
3 
Scoring PSQI 


85 
 
 
Component 
Number 
Criteria 
Values 
 
Total Score Scale 
Component Score 
Component 1 
 
Q9 
 
(Q9): ______ 
 
 
N/A 
 
___ 
 
Component 2 
Q2 + Q5a 
 
Question 2 Scale: 
Time              Score 
<15 min         0 
16-30 min      1 
31-60 min      2 
>60 min         3 
 
 
 
 
(Q2): ______ + (Q5a): _____ = _____ 
 
 
Sum         Score 
0               0   
1-2           1 
3-4           2 
5-6           3 
 
 
 
 
 
 
___ 
 
Component 3 
 
Q4 
 
(Q4): ______ 
 
 
N/A 
 
___ 
 
Component 4 
 
#hours slept     X 100% 
#hours in bed 
 
Look at Q1,3, and 4 for 
these values 
 #hours slept:   ____   X 100% = _____ 
#hours in bed: 
%             Score 
>85%        0   
75-85%    1 
65-75%    2 
<65%        3 
 
 
 
___ 
 
Component 5 
 
 
 
 
Sum of Q5b through Q5j 
     (Q5b): ______ 
     (Q5c): ______ 
     (Q5d): ______ 
     (Q5e): ______ 
     (Q5f): ______ 
     (Q5g): ______ 
     (Q5h): ______ 
     (Q5i): ______ 
+   (Q5j): ______         =  ______ 
 
 
 
Sum         Score 
0               0   
1-9           1 
10-18       2 
19-27       3 
 
 
 
 
 
 
 
 
___ 
 


86 
 
Component 6 
 
Q6 
 
(Q6): ______ 
 
 
N/A 
 
___ 
 
Component 7 
 
 
 
 
Q7 + Q8 
 
(Q7): ______ + (Q8): _____ = _____ 
 
Sum         Score 
0              0   
1-2           1 
3-4           2 
5-6           3 
 
 
 
___ 
 
Total Score (Sum of Components 1-7):  ___ 
 
 
 


87 
 
APPENDIX 16: Brief Agitation Measure90 
Instructions: Please read each item below and indicate to what extent you feel the statement describes you. 
Rate each statement on the scale below: 
 
 
Strongly 
Disagree 
Disagree 
Somewhat 
disagree 
Neither  agree  
nor disagree 
Somewhat 
agree 
Agree 
Strongly 
Agree 
1)Recently, I want to crawl 
out of my skin 
0 
1 
2 
3 
4 
5 
6 
2) Recently, I feel so stirred 
up inside I want to scream 
0 
1 
2 
3 
4 
5 
6 
3) Recently, I feel a lot of 
emotional turmoil in my 
gut 
0 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
 
 
 


88 
 
APPENDIX 17: End of Treatment Follow-Up - Side Effects Questionnaire 
 
Have you experienced any side effects following the end of treatment over the last two weeks?   Yes   
No 
If yes, could you please describe the side effect you are experiencing, its frequency and severity: 
 
 
 
 


89 
 
 
APPENDIX 18: SCOFF Questionnaire (Eating Disorder Screen)18 
 
S – Do you make yourself Sick because you feel uncomfortably full?  
 
  Yes       No 
 
C – Do you worry you have lost Control over how much you eat?  
 
  Yes       No 
 
O – Have you recently lost more than 14 pounds (lbs) in a three-month period?  
 
  Yes       No 
 
F – Do you believe yourself to be Fat when others say you are too thin?  
 
  Yes       No 
 
F – Would you say Food dominates your life?  
 
  Yes       No 
 
An answer of ‘yes’ to two or more questions warrants further questioning and more comprehensive assessment 
 
 
 A further two questions have been shown to indicate a high sensitivity and specificity for bulimia nervosa. These questions 
indicate a need for further questioning and discussion.  
 
1. Are you satisfied with your eating patterns?  
  Yes       No 
 
2. Do you ever eat in secret? 
 
  Yes       No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


90 
 
APPENDIX 19: Mood Disorder Questionnaire (MDQ)91 
 
Has there ever been a period of time when you were not your usual self and… 
Yes 
No 
... you felt so good or so hyper that other people thought you were not your normal self, 
or you were so hyper that you got into trouble? 
 
 
... you were so irritable that you shouted at people or started fights or arguments? 
 
 
... you felt much more self-confident than usual? 
 
 
... you got much less sleep than usual and found you didn’t really miss it? 
 
 
... you were much more talkative or spoke much faster than usual? 
 
 
... thoughts raced through your head or you couldn’t slow your mind down? 
 
 
... you were so easily distracted by things around you that you had trouble concentrating 
or staying on track? 
 
 
... you had much more energy than usual? 
 
 
... you were much more active or did many more things than usual? 
 
 
... you were much more social or outgoing than usual; for example, you telephoned 
friends in the middle of the night? 
 
 
... you were much more interested in sex than usual? 
 
 
... you did things that were unusual for you or that other people might have thought 
were excessive, foolish, or risky? 
 
 
... spending money got you or your family into trouble? 
 
 
If you checked YES to more than one of the above, have several of these ever happened 
during the same period of time? 
 
 
How much of a problem did any of these cause you- like being unable to work; having 
family, money, or legal troubles, getting into arguments or fights? 
 
 
No Problems 
Minor Problems 
Moderate Problems 
Serious Problems  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


91 
 
APPENDIX 20: Modified Mini Screen (MMS) (Psychotic Disorders)17 
 
 
Please select “Yes” or “No” for each question 
Yes 
No 
Have you ever believed that people were spying on you, or that someone was plotting 
against you, or trying to hurt you? 
 
 
Have you ever believed that someone was reading your mind or could hear your 
thoughts, or that you could actually read someone’s mind or hear what another 
person was thinking? 
 
 
Have you ever believed that someone or some force outside of yourself put thoughts 
in your mind that were not your own, or made you act in a way that was not your 
usual self? Or, have you ever felt that you were possessed? 
 
 
Have you ever believed that you were being sent special messages through the TV, 
radio, or newspaper? Did you believe that someone you did not personally know was 
particularly interested in you? 
 
 
Have your relatives or friends ever considered any of your beliefs strange or unusual? 
 
 
Have you ever heard things other people couldn’t hear, such as voices? 
 
 
Have you ever had visions when you were awake or have you ever seen things other 
people couldn’t see? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


92 
 
APPENDIX 21: Columbia Suicide Severity Rating Scale (C-SSRS) 92 
 


93 
 
 
 


94 
 
APPENDIX 22: Brief Psychiatric Rating Scale (BPRS)93 
The Study Clinician 
(MD/PA) will conduct an interview with the participant that addresses the 18 symptom constructs found below. Each construct 
will be assessed on a scale of 0 to 7, zero indicating “not assessed” and 7 indicating “extremely severe” symptoms.  
 
 
 
 


95 
 
APPENDIX 23: Perceived Stress Scale (PSS-4)94 
Instructions: The questions in this scale ask you about your feelings and thoughts during the last 
month.  In each case, please indicate with a check how often you felt or thought a certain way.  
  
1.  In the last month, how often have you felt that you were unable to control the important things in your 
life? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often  
 
2.  In the last month, how often have you felt confident about your ability to handle your personal 
problems? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
3.  In the last month, how often have you felt that things were going your way? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
4.  In the last month, how often have you felt difficulties were piling up so high that you could not 
overcome them? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
 
 
 
 
 
 
 
 
 
 
 


96 
 
APPENDIX 24: Modified Cigarette Evaluation Questionnaire (mCEQ)95 
 
 If you have smoked since you last completed this questionnaire, please mark the number that best 
represents how smoking made you feel. 
 (1—not at all, 2—very little, 3—a little, 4—moderately, 5—a lot, 6—quite a lot, 7—extremely). 
1. Was smoking satisfying? _____ 
2. Did cigarettes taste good? _____ 
3. Did you enjoy the sensations in your throat and chest? _____ 
4. Did smoking calm you down? _____ 
5. Did smoking make you feel more awake? _____ 
6. Did smoking make you feel less irritable? _____ 
7. Did smoking help you concentrate? _____ 
8. Did smoking reduce your hunger for food? _____ 
9. Did smoking make you dizzy? _____ 
10. Did smoking make you nauseous? _____ 
11. Did smoking immediately relieve your craving for a cigarette? _____ 
12. Did you enjoy smoking? _____ 
 
 
 
 
 
 
 


97 
 
APPENDIX 25: Demographics Form 
 
Basic Demographics 
 
Age ___________    Date of Birth _______________________ 
 
Gender:  Male      Female       Transgender Female 
Transgender Male     Prefer not to answer 
 
Race 
 White 
 Black or African American 
 Asian 
 Native Hawaiian or Other Pacific Islander 
 American Indian or Alaska Native 
 Other 
 More than one race 
 
Ethnic  
Category      
 
 
 Hispanic or Latino      Not Hispanic or Latino 
 
 
What is the highest level of schooling you have completed?  
 Elementary school or less 
 Some high school 
 High school graduate or equivalent 
 Some college or technical/vocational school 
 College graduate or higher 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
98 
 
APPENDIX 26: Contact information Form 
 
 
Contact Information Form 
Please fill in the following information about yourself: 
First Name ___________________    M.I. _______    Last Name ________________________ 
Number and Street Address ____________________________________________________ 
City___________________________    State _________    Zip code _____________________ 
Email address ________________________________________________________________ 
Primary Telephone # ___________________    Other Telephone # ______________________ 
Do you give CSC permission to leave a message at the above numbers or contact you by email? 
 Yes  
 No   
If I cannot be reached or if there is an emergency, you can leave a message with: 
Name _____________________________________     Telephone # _____________________ 
 
I understand in the event that I do not return messages and fail to come to appointments my 
emergency contact person may be contacted. 
 
Participant’s Signature _________________________________    Date __________________ 
 
 
 
 
 
 
 


 
99 
 
APPENDIX 27: Review of Systems (ROS) 
 
 
 


 
100 
 
 
 
 
 
 
 
 
 
 
 
 


 
101 
 
APPENDIX 28: Alcohol Use Disorders Identification Test (Audit-C) 
 
1. How often do you have a drink containing alcohol?  
(0) Never  
(1) Monthly or less  
(2) 2 to 4 times a month  
(3) 2 to 3 times a week 
(4) 4 or more times a week 
 
2. How many drinks containing alcohol do you have on a typical day when you are drinking? 
(0) 1 or 2 
(1) 3 or 4  
(2) 5 or 6  
(3) 7, 8, or 9 
(4) 10 or more  
 
3. How often do you have six or more drinks on one occasion? 
(0) Never 
(1) Less than monthly  
(2) Monthly  
(3) Weekly 
(4) Daily or almost daily 
 
 
TOTAL          4 or greater for men is considered a positive screen; 3 or greater for women is 
considered a positive screen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
102 
 
APPENDIX 29: 6 Week Follow-Up Smoking Status Questions  
 
Finally, I have two additional questions I would like to ask you about your recent smoking history.  
1. In the last 7 days, have you smoked at all – even a puff?  О Yes    О No 
2. In the last 7 days, how many cigarettes, on average, have you smoked per day?  ________ 
 
If the participant answers “NO” to question 1 and zero cigarettes to question 2, ask the 
participant when they smoked their last cigarette: 
 
When was the date of your last cigarette?  ________________________