Clinical trial NCT04188106
Conditions: Smoking Cessation Stress Sleep Disturbance Nausea
Sponsor: Rose Research Center, LLC
Start date: 2019-06-17; Completion date: 2019-12-15
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label study will evaluate hydroxyzine, a first-generation antihistamine, combined with varenicline, to help smokers abstain from smoking during a 12-week trial period by diminishing the nausea, stress, anxiety, and sleep disturbances associated with the use of varenicline and with nicotine withdrawal.

Detailed description:

Arms: arm 1: Participants enrolled in the study will take the FDA approved starter kit of varenicline for the first week of medication administration (0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7). During the first week, participants will also receive hydroxyzine dosed in a similar manner, 50 mg nightly for the first 3 days, then twice daily, 25 mg in the morning and 50 mg at night. After the first week, participants will receive the FDA-approved dose of varenicline (1 mg twice daily) combined with hydroxyzine, 25 mg in the morning and 50 mg at nighttime. All medications will be dosed orally.
Interventions: intervention 1: Varenicline Pill intervention 2: Hydroxyzine Pill
Intervention descriptions: intervention 1: FDA approved starter kit of varenicline (0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7) followed by FDA-approved dose of varenicline (1 mg twice daily) for the remaining 11 weeks intervention 2: For the first week, participants will receive 50 mg nightly for the first 3 days, then twice daily, 25 mg in the morning and 50 mg at night for the remaining 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Efficacy and Tolerability of Combination 
Varenicline With Hydroxyzine as a Potential 
Smoking Cessation Treatment (HAVE) 
 
NCT04188106 
 
Protocol V1.1 
04 Jun 2019 


Main Office • 7920 ACC Blvd., Suite 110 • Raleigh, NC 27617 
 
 
Clinical Study Protocol 
 
 
Study Title: 
Efficacy and tolerability of combination varenicline with 
hydroxyzine as a potential smoking cessation treatment 
Sponsor: 
 
 
Foundation for a Smoke-Free World 
Version Number:   
Version 1.1 
Version Date:  
 
04 June 2019 
Principal Investigator: 
Jed E. Rose, Ph.D. 
Medical Supervision:  
Perry Willette, MD 
Authors: 
Jed E. Rose, Ph.D.,  
President and CEO, 
Rose Research Center 
 
Perry Willette, MD 
Medical Director,  
Rose Research Center 
Tanaia Loeback 
Executive Vice President,  
Rose Research Center 
 
David Botts 
Executive Vice President,  
Rose Research Center 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the applicable provisions of United States law. No part of this document may be publicly disclosed without the written consent 
of the Rose Research Center, LLC. 
 
 


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PROTOCOL HISTORY 
Date 
Description 
15 May 2019 
Initial Version submitted to IRB on 24 May 2019 
04 June 2019 
Protocol Amendment 1: 
Clarification of follow up after dose adjustment (see 
Section 2.1 on page 9, Section 5.4 on page 18, and 
Section 6.3 on page 19). “Participants will be 
contacted with a follow-up call by Research Medical 
Staff within 72 hours of any dose adjustment.” 
 
 
 


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TABLE OF CONTENTS 
List of Abbreviations ..................................................................................................................................... 6 
 
Introduction .......................................................................................................................................... 8 
1.1 
Study Design and Plan .................................................................................................................. 8 
1.2 
Background ................................................................................................................................... 8 
 
Study Objectives and Endpoints ........................................................................................................... 9 
2.1 
Efficacy of Varenicline and Hydroxyzine for Stress and Sleep ...................................................... 9 
2.2 
Effects of Varenicline on Smoking Reduction prior to the Quit Date ......................................... 10 
2.3 
Identify Additional Early Predictors of Treatment Outcome ..................................................... 10 
 
Investigational Plan ............................................................................................................................ 11 
3.1 
Study Design ............................................................................................................................... 11 
3.2 
Study Plan ................................................................................................................................... 12 
3.3 
Point of Enrollment .................................................................................................................... 12 
3.4 
Study and Session Durations ...................................................................................................... 12 
 
Participant Involvement ..................................................................................................................... 13 
4.1 
Selection of Study Population .................................................................................................... 13 
4.2 
Recruitment Strategies ............................................................................................................... 14 
4.3 
Participant Retention in the Study ............................................................................................. 15 
4.4 
Discontinuation of Participants from Study ............................................................................... 15 
4.5 
Lost to Follow-up ........................................................................................................................ 15 
4.6 
Violation of Inclusion/Exclusion Criteria .................................................................................... 15 
4.7 
Participant Compensation .......................................................................................................... 15 
4.8 
Session and Response Windows ................................................................................................ 16 
 
Hydroxyzine ........................................................................................................................................ 16 
5.1 
Description of Hydroxyzine ........................................................................................................ 16 
5.2 
Hydroxyzine Product Use Timeframe ......................................................................................... 17 
5.3 
Dosage ........................................................................................................................................ 17 
5.4 
Dose Adjustment Procedures ..................................................................................................... 18 
5.5 
Accountability and Compliance .................................................................................................. 18 
 
Varenicline .......................................................................................................................................... 18 
6.1 
Description of Varenicline .......................................................................................................... 18 
6.2 
Dosage ........................................................................................................................................ 18 


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6.3 
Dose Adjustment Procedures ..................................................................................................... 19 
6.4 
Accountability and Compliance .................................................................................................. 19 
 
Study Procedures and Activities ......................................................................................................... 19 
7.1 
Informed Consent and Guidance................................................................................................ 19 
7.2 
Safety Laboratory and Other Assessments ................................................................................ 20 
 
Sessions .............................................................................................................................................. 25 
8.1 
Screening Session (V1) ................................................................................................................ 25 
8.2 
5-day observation period ........................................................................................................... 26 
8.3 
Pre-Quit Session (V2) .................................................................................................................. 26 
8.4 
Day before quit date (V3) ........................................................................................................... 26 
8.5 
Post-Quit Sessions (V4-V7) ......................................................................................................... 27 
8.6 
6-Month Follow Up ..................................................................................................................... 28 
8.7 
Schedule of Events ..................................................................................................................... 28 
8.8 
SMS Messaging ........................................................................................................................... 29 
 
Risk / Benefit Information .................................................................................................................. 29 
9.1 
Potential Benefits ....................................................................................................................... 29 
9.2 
Importance of Knowledge to be Gained .................................................................................... 30 
9.3 
Potential Risks ............................................................................................................................ 30 
9.4 
Protection Against Risks ............................................................................................................. 31 
 Quality Control and Quality Assurance .............................................................................................. 31 
10.1 
Training of Staff .......................................................................................................................... 31 
10.2 
Audits and Inspections ............................................................................................................... 31 
 Reporting of Adverse Events .............................................................................................................. 32 
11.1 
Definitions .................................................................................................................................. 32 
11.2 
Collection of Safety Events from Participants ............................................................................ 32 
11.3 
Assessment of Adverse Events ................................................................................................... 33 
11.4 
Follow-up of Non-serious and Serious Adverse Events .............................................................. 34 
11.5 
Reporting of Safety Events to IRB ............................................................................................... 34 
11.6 
Reporting of Safety Events to FDA ............................................................................................. 34 
11.7 
Reporting and Follow-Up of Pregnancies ................................................................................... 34 
11.8 
Adverse Event Leading to Discontinuation ................................................................................. 34 
 Data Management .............................................................................................................................. 34 
12.1 
Data Collection Procedures ........................................................................................................ 34 


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12.2 
Protocol Deviations / Noncompliance ........................................................................................ 35 
12.3 
Data Capture ............................................................................................................................... 35 
12.4 
Missing Data ............................................................................................................................... 36 
12.5 
Data Handling ............................................................................................................................. 36 
12.6 
Data Validation ........................................................................................................................... 36 
12.7 
Database Lock ............................................................................................................................. 36 
 Planned Statistical Methods ............................................................................................................... 36 
13.1 
Efficacy and Tolerability.............................................................................................................. 36 
13.2 
Interim Analysis .......................................................................................................................... 38 
 Ethics and Regulations ........................................................................................................................ 38 
14.1 
IRB Approval ............................................................................................................................... 38 
14.2 
Investigational New Drug Application ........................................................................................ 38 
14.3 
GCP and Regulatory Requirements ............................................................................................ 39 
14.4 
Participant Information and Consent ......................................................................................... 39 
14.5 
Amendment to Informed Consent Form .................................................................................... 39 
 Administrative Considerations ........................................................................................................... 39 
15.1 
Participant Confidentiality .......................................................................................................... 39 
15.2 
Record Retention ........................................................................................................................ 40 
 References .......................................................................................................................................... 41 
 
APPENDIX 
Appendix 1 -10-Item Perceived Stress Scale (PSS-10) ................................................................................ 44 
Appendix 2 - 6-Item State-Trait Anxiety Inventory (STAI) .......................................................................... 45 
Appendix 3 - The Patient Health Questionnaire (PHQ-9) ........................................................................... 46 
Appendix 4 - Minnesota Nicotine Withdrawal Scale (MNWS) ................................................................... 47 
Appendix 5 - Fagerström Test for Nicotine Dependence (FTND) ............................................................... 48 
Appendix 6 - The Wisconsin Predicting Patients' Relapse Questionnaire (WI-PREPARE) .......................... 49 
Appendix 7 - Research Participant Payment Verification Form ................................................................. 50 
Appendix 8 - Smoking History .................................................................................................................... 51 
Appendix 9 - Registration Form .................................................................................................................. 52 
Appendix 10 - Medical History Form .......................................................................................................... 53 
Appendix 11 - Review of Systems Form ..................................................................................................... 58 
Appendix 12 - Employment History ............................................................................................................ 60 
Appendix 13 - Adverse Effects Form .......................................................................................................... 62 
Appendix 14 - Daily SMS Survey ................................................................................................................. 63 
Appendix 15 - USPHS Quit Smoking Handout (modified) .......................................................................... 64 


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Appendix 16 - SMS Observation Survey (after enrollment - prior to V2) ................................................... 66 
Appendix 17 - Participant Instructions for Hydroxyzine ............................................................................ 67 
Appendix 18 - Participant Instructions for Varenicline .............................................................................. 68 
Appendix 19 - 6-Month Follow Up Survey ................................................................................................. 69 
Appendix 20 - Modified Cigarette Evaluation Questionnaire (mCEQ) ....................................................... 70 
 
 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
ASP 
Application Service Provider 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CC 
Conventional cigarette 
CDC 
Center for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CO 
Carbon monoxide 
CRF 
Case report form 
CRM 
Customer relationship management 
ECG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration  
FTND 
Fagerström test for nicotine dependence 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
ICF 
Informed consent form 


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ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
Kg 
Kilograms 
Lbs 
pounds 
QTc 
Corrected QT interval 
mCEQ 
Modified Cigarette Evaluation Questionnaire. 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
Mg 
Milligram 
mL 
Milliliter 
nAChR 
Nicotinic Acetylcholine Receptor 
MNWS 
Minnesota Nicotine Withdrawal Scale 
PHQ-9 
The Patient Health Questionnaire 
PPM 
Parts per million 
RBC 
Red blood cell (count) 
RCT 
Randomized Control Trial 
RRC 
Rose Research Center, LLC. 
SaaS 
Software-as-a-Service 
SAE 
Serious adverse event 
SMS 
Short Message Service 
SOP 
Standard operating procedure 
SSL 
Secure Sockets Layer 
STAI 
State-Trait Anxiety Inventory 
TLS 
Transport Layer Security 
V 
Voltage 
W 
Wattage 
WBC 
White blood cell (count) 


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WHO 
World Health Organization 
WI-PREPARE 
The Wisconsin Predicting Patients' Relapse Questionnaire 
 INTRODUCTION 
1.1 STUDY DESIGN AND PLAN 
This open-label study will evaluate hydroxyzine, a first-generation antihistamine, combined with varenicline, to 
help smokers abstain from smoking during a 12-week trial period by diminishing the nausea, stress, anxiety, and 
sleep disturbances associated with the use of varenicline and with nicotine withdrawal. 
1.2 BACKGROUND 
Cigarette smoking remains the leading cause of preventable death in the U.S., and is one of the leading causes of 
preventable morbidity and mortality.1,2 An estimated 540,000 smokers die each year from smoking-related 
diseases.3 Existing treatments for tobacco cessation yield, on average, less than 25% long-term abstinence rates, 
with many of the cessation failures occurring within the first month of abstinence.4 There is an urgent need to 
develop new therapies for smoking cessation, including repurposing FDA-approved medications.5 Current 
pharmacological approaches (e.g. nicotine replacement therapy, bupropion, or varenicline) increase efficacy for 
smoking cessation, but continue to have poor long-term abstinence rates, with potentially concerning adverse 
events. 
Research into the predictors of smoking lapse, the initial step in smoking relapse and unsuccessful quit attempts, 
demonstrate the importance of stress as it relates to smoking cessation.6 In 2011, McKee, et. al. demonstrated 
that stress decreases the ability to resist smoking.7 An individual’s response to stress from the discomfort of 
nicotine withdrawal and quitting smoking (so called “distress tolerance”) may be an important factor in 
successful and persistent abstinence from smoking.8 Additionally, sleep disturbances during smoking cessation, 
either as a withdrawal symptom from nicotine, or as a side effect of treatment medications (like varenicline), 
may play an important role in failed smoking cessation attempts.9 One of the most successful medications, 
varenicline, a full agonist on α7-nicotinic acetylcholine receptors (nAChRs) and a partial agonist on 
the α4β2, α3β4, and α6β2 subtypes, has side effects which include nausea, difficulty sleeping, and 
nightmares.10–12 
Hydroxyzine is an FDA approved first-generation antihistamine of the diphenylmethane and piperazine class that 
has antiemetic, anxiolytic, and sedative effects. Hydroxyzine’s effects are primarily derived due to its actions as a 
potent H1 receptor inverse agonist. It also acts as an antagonist on the 5-HT2A, D2, and α1-adrenergic 
receptors. Because of its antiserotonergic effects, as well as the antagonistic effects on multiple receptor 
systems in the brain, hydroxyzine is noted to have strong anxiolytic properties, as well as mild antiobsessive and 
antipsychotic properties. Even with its effective sedative, hypnotic, and anxiolytic effects, hydroxyzine does not 
demonstrate any of the abuse, dependence, addiction or toxicity potential associated with medications within 
the same therapeutic range (such as benzodiazepines or nonbenzodiazepine hypnotics).13  
In vitro studies point to the important role of H1 receptor antagonist (antihistamines) on the functional 
properties of cloned α7- nicotine acetylcholine receptor expressed in Xenopus oocytes.14 Recent clinical trials 
have investigated antihistamines as potential aids in quitting smoking. This includes animal models which 


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evaluated the effects of the antihistamine pyrilamine (a centrally acting first-generation antihistamine) on 
Sprague-Dawley rats self-administering nicotine. This study showed significant reductions in nicotine self-
administration with both acute dosing and repeated injections of this centrally acting antihistamine.15(p1) A 
recent study at Duke University evaluated meclizine (a first-generation nonselective H1 antagonist) as a 
potential smoking cessation treatment. In this phase II study completed in 2013, participants were given a 
divided dose of meclizine (either 25 mg a day or 50 mg a day, administered in two doses each day) with a 
nicotine patch for three weeks during the pre-quit period. The study results demonstrate the high potential for 
this class of medications to provide improved rates of abstinence for smokers who desire to quit.16 As opposed 
to hydroxyzine, meclizine is not recognized to have anxiolytic properties, and has a much shorter half-live, only 
six hours, compared to hydroxyzine which has a half-life of about 20 hours.17,18 
This study investigates the potential for decreasing the rate of adverse effects of varenicline and increasing the 
efficacy of varenicline when it is combined with hydroxyzine. Since hydroxyzine is an FDA-approved medication, 
marketed in the United States, it does not require an IND (Investigational New Drug) application. This study is 
not intended to support a new indication, support a change in labeling, support a change in advertising, nor 
does it involve a change in dosage level or route of administration. 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1 EFFICACY OF VARENICLINE AND HYDROXYZINE FOR STRESS AND SLEEP 
A maximum of fifty (50) smokers will receive the FDA-approved dosing for both varenicline and hydroxyzine. 
These medications have been approved by the FDA for use by healthy, non-pregnant adults at the doses and 
frequencies specified in this study.  
Participants enrolled in the study will take the FDA approved starter kit of varenicline for the first week of 
medication administration (0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7). During the first 
week, participants will also receive hydroxyzine dosed in a similar manner, 50 mg nightly for the first 3 days, 
then twice daily, 25 mg in the morning and 50 mg at night. After the first week, participants will receive the FDA-
approved dose of varenicline (1 mg twice daily) combined with hydroxyzine, 25 mg in the morning and 50 mg at 
nighttime. All medications will be dosed orally. The FDA has approved the 50 mg dose of hydroxyzine for 
treatment of nausea, anxiety, and insomnia. The morning dose of hydroxyzine is limited to 25 mg to minimize 
the sedative effects of this antihistamine, while the evening dose is prescribed at 50 mg to maximize the 
antiemetic, anxiolytic, and sedative properties. Dose adjustments for hydroxyzine by licensed medical providers 
may occur based on adverse effects reported by participants (e.g. daytime sedation…stop the AM dose of 
hydroxyzine, difficulty waking in the am…decrease nighttime dose of hydroxyzine). Participants will be contacted 
with a follow-up call by Research Medical Staff within 72 hours of any dose adjustment. Trial medications will 
continue until the participant returns for the End-of-Study visit, approximately 12 weeks after initiation of the 
medications.  
2.1.1 Stress 
Stress levels will be measured using the 10-item Perceived Stress Scale (PSS-10) at each laboratory session.  
2.1.2 Anxiety and Depression 
Anxiety levels and depression will be monitored using the 6-item State-Trait Anxiety Inventory (STAI) and the 
Patient Health Questionnaire (PHQ-9) provided during each laboratory sessions. 


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2.1.3 Additional Monitoring 
Participants will respond to the Fagerström Test for Nicotine Dependence (FTND) and the Minnesota Nicotine 
Withdrawal Scale at each laboratory session after enrollment. Participants will also respond to the Modified 
Cigarette Evaluation Questionnaire (mCEQ, satisfaction with smoking) and the “Wisconsin Predicting Patients’ 
Relapse” questionnaire (WI-PREPARE, susceptibility to smoking relapse) at Visit 2 and Visit 3. Spontaneous 
reduction in ad libitum smoking will be monitored with daily cigarette-use diaries, via SMS text messages. Data 
collection will begin upon enrollment and continuing until the End-Of-Study visit.  
2.1.4 Side Effects and Tolerability data 
Tolerability will be evaluated using open-ended as well as targeted side effect assessments at each visit. 
Participants will be queried on their level of nausea via daily SMS text messages. 
2.2 EFFECTS OF VARENICLINE ON SMOKING REDUCTION PRIOR TO THE QUIT DATE 
Previous research has shown that abstinence at the end of treatment is strongly predicted by the extent to 
which smokers spontaneously reduce ad libitum smoking in the initial weeks of pharmacotherapy that is 
initiated before the quit-smoking date. This finding was initially discovered by the principal investigator (2009) 
using pre-quit date nicotine skin patch treatment and has been extended by other investigators who have found 
similar results using bupropion and varenicline. This early marker of subsequent success can be extremely useful 
in clinical practice by helping to guide adaptive changes in treatment before a potential relapse occurs. We will 
assess the extent of smoking reduction in participants during the initial seven days of treatment (prior to their 
planned quit date) through the End-Of-Study, indexed by smoking diaries and biochemical measures (expired air 
carbon monoxide). We will correlate these reductions with abstinence assessed at the end of treatment. 
2.3 IDENTIFY ADDITIONAL EARLY PREDICTORS OF TREATMENT OUTCOME 
In addition to pre-quit reductions in ad libitum smoking, several other variables will be assessed in the first week 
before the quit-smoking date and correlated with end-of-treatment abstinence. These measures include: a) 
subjective ratings of the rewarding effects of smoking, craving for cigarettes and other nicotine withdrawal 
symptoms, assessed using standardized questionnaires; b) demographic measures, including gender, age, 
socioeconomic status, and race; and c) smoking history variables, including baseline cigarette consumption, level 
of nicotine dependence, and number of prior quit attempts. 
2.3.1 Self-report of Smoking Behaviors and Nicotine dependence 
Number of cigarettes smoked per day will be evaluated using daily diaries. Nicotine dependence measures will 
be taken using the Fagerström Test for Nicotine Dependence (FTND).22 
2.3.2 Self-reported Rewarding / Aversive Effects of Cigarettes 
Rewarding and aversive effects will be evaluated using the validated modified Cigarette Evaluation 
Questionnaire (mCEQ)23, initially developed in the Principal Investigator’s laboratory. The mCEQ assesses the 
degree to which participants experience the reinforcing effects of smoking, providing five subscale scores: 
smoking satisfaction (satisfying, tastes good, enjoy smoking), psychological reward (calms down, more awake, 
less irritable, helps concentrate, reduces hunger), aversion (dizziness, nauseated), enjoyment of respiratory tract 
sensations (single-item assessment), and craving reduction (single-item assessment).  


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 INVESTIGATIONAL PLAN 
3.1 STUDY DESIGN 
This study design has been developed to hasten the identification and evaluation of promising new smoking 
cessation treatments. This single-group, small-scale, open-label study (N= maximum of 50) will evaluate 
hydroxyzine combined with varenicline. The rate of nausea reported in this study will be compared to the known 
nausea rates associated with varenicline alone (~30%). Interim data analysis will occur after 25 participants have 
reached the primary outcome. In choosing these thresholds, Monte Carlo simulations were conducted to 
determine the significance thresholds for both the N=25 and N=50 one-tailed binomial tests so that the overall 
false positive (Type I error) rate across all tests would be approximately 10%. Conversely, the overall false 
negative (Type II error) rate, whereby a promising treatment is discarded prematurely, would be approximately 
20%. These initial results will fall into one of three categories: 
3.1.1 Reported nausea 12% or less of participants 
If three or less participants report nausea with combination hydroxyzine and varenicline, this investigational 
treatment will be viewed as having considerable promise and will immediately be advanced to a larger-scale 
(~N=200) randomized controlled clinical trial (RCT) and this “pilot” study will stop recruitment. This RCT will be 
submitted as a separate protocol. 
3.1.2 Reported nausea in 16% to 24% of participants 
If 4 to 6 participants report nausea with combination hydroxyzine and varenicline, an additional 25 participants 
will be recruited to obtain a more precise estimate of the success rate. If, cumulatively, reported nausea is less 
than 20% (10/50), the combination of hydroxyzine and varenicline will be advanced to a larger-scale (~N=200) 
RCT. 
3.1.3 Reported nausea in at least 28% of participants 
If 7 or more participants report nausea with combination hydroxyzine and varenicline, this investigational 
treatment will be viewed unpromising and no additional participants will be enrolled. 


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3.1.4 Stepwise Evaluation Algorithm   
3.2 STUDY PLAN 
After obtaining informed consent, adult smokers will be enrolled into the study. There will be an observational 
period of at least five days to obtain baseline data on use of combustible cigarettes and stress/anxiety and 
nausea symptoms. 
 
Figure 
1 - 
Overall 
Study 
Design 
3.3 POINT OF ENROLLMENT 
Participants will be enrolled after screening once all safety laboratory results have been received and reviewed 
by the medical staff (MD or PA). Study drugs will be dispensed starting at V2, and at each subsequent visit until 
the End-Of-Study. 
3.4 STUDY AND SESSION DURATIONS 
The expected duration of the study, from first participant, first visit, through last participant, last visit will be 
approximately one year. The total duration for a participant will be approximately 14-16 weeks. 
• 
The Screening Session (Visit 1) will last approximately three hours. 
• 
The other study sessions will last approximately one hour. 
Pilot Study 
(enroll 25 participants)
Incidence of Nausea vs Benchmark
0-3 of 25
(≤ 12% vs 30%)
Proceed to RCT
Incidence of Nausea vs Benchmark
4-6 of 25
(16-24% vs 30%)
Enroll an additional 25 subjects
Incidence of Nausea vs Benchmark
≤ 10 of 50
(≤ 20% vs. 30%)
Proceed to RCT
Incidence of Nausea vs Benchmark
> 10 of 50
(> 20% vs 30%)
Terminate Study
Incidence of Nausea vs Benchmark
≥ 7 of 25
(≥28% vs 30%)
Terminate Study
Call to Enroll
Week 1
Week 2
Week 3/4
Week 5-8
Week 9-12
Start 5+ day
Varenicline
Varenicline
Observational
Starter Pack
Standard Dose
Thru EOS
Period
with Hydroxyzine
with Hydroxyzine
V1
approx
2-3 days
V2
V3
V4
V5
V6
V7
Quit day
Varenicline Dose     = 0.5 mg QPM x 3 days, then 0.5 mg BID x 4 days, then 1.0 mg BID x 11 weeks
Hydroxyzine Dose   =  50 mg QPM x 3 days, then 25 mg QAM + 50 mg QPM
Screening
Verify 
Eligility


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 PARTICIPANT INVOLVEMENT 
4.1 SELECTION OF STUDY POPULATION 
Healthy, cigarette smoking adults, age 19-65 years, with no restriction on gender, race and ethnicities, or social-
economic status, who have smoked an average of at least 10 commercially available cigarettes per day for the 
last 12 months will be screened for enrollment in this study. 
The study will screen and enroll at both Rose Research Center locations, located in Raleigh and Charlotte, North 
Carolina. 
4.1.1 Inclusion Criteria 
Each participant must meet all the following inclusion criteria before enrollment: 
Inclusion Criteria 
1. Has signed the ICF and is able to read and understand the information provided in the ICF.  
2. Is 19 to 65 years of age (inclusive) at screening.  
3. Smokes at least 10 commercially available cigarettes per day for the last 12 months. 
4. Has an expired air CO reading of at least 10 ppm at screening. 
5. Express a desire to quit smoking within the next 30 days at screening. 
6. Willing and able to comply with the requirements of the study. 
7. Participant owns a smart phone with text message and data capabilities. 
4.1.2 Exclusion Criteria 
Potential participants who show or report indications of or self-report a diagnosis of conditions listed below may 
be excluded from the study. If the study physician (or designee) determines through the course of pre-screening, 
or a physical screen, medical history, physical findings, current medications, ECG, or laboratory findings suggests 
one of the conditions listed below, or findings reveal other information that may potentially jeopardize the 
participants’ safe participation, then they may be excluded. For medical conditions that do not appear below, 
the participant may be enrolled if the study physician (or designee) does not feel that the medical condition 
would jeopardize safe study participation or data validity. 
Exclusion Criteria 
1. Is unhealthy or cannot participate in the study for any reason (e.g., medical, psychiatric, and/or social 
reason) as judged by the Investigator or designated medical staff based on all available assessments from 
the screening period (e.g., safety laboratory, vital signs, physical examination, ECG, concomitant 
medications and medical history).   
2. PHQ-9 score greater than 9, or a score greater than 0 on item #9 (“Thoughts that you would be better off 
dead, or of hurting yourself in some way”) at screening. 
3. High blood pressure (systolic > 150 mmHg or diastolic >95 mmHg) at screening.  


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Exclusion Criteria 
4. Body mass index (BMI) less than 15.0 kg/m2 or greater than 40.0 kg/m2. 
5. Coronary heart disease, structural cardiac disease, cardiac dysrhythmias, abnormal ECG (e.g. prolonged 
QTc), syncope, cardiac chest pain, or history of heart attack or heart failure. 
6. Has received psychotherapy or behavioral treatments potentially impacting symptoms of depression, 
anxiety, or nicotine withdrawal within 30 days of screening, or during the study.  
7. Taking antidepressants, psychoactive medications (e.g. antipsychotics, benzodiazepines, hypnotics) or 
medications that prolong QTc. 
8. Positive urine drug test for cocaine, THC, opiates, amphetamines or methamphetamines.   
9. Use of smokeless tobacco (chewing tobacco, snuff), cigars, pipes, hookah, e-cigarettes, nicotine 
replacement therapy or other smoking cessation treatments within 14 days of enrollment. 
10. Pregnant or nursing (by self-report) or has a positive pregnancy test. 
4.1.3 Women of Childbearing Potential 
Pregnant or breastfeeding women will be excluded from the study. All females will undergo a serum pregnancy 
test at screening (Visit 1) and a urine pregnancy test at each subsequent visit. Heterosexually active females of 
childbearing potential (not post-menopausal) must agree to use medically acceptable contraceptives during the 
study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, 
hysterectomy, or Essure), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine 
device (IUD).  Contraceptive measures such as Plan BTM, sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. Female participants will be encouraged in the consent form to notify study 
staff if they believe a change in their pregnancy status has occurred during the trial.  
Post-menopause is defined as the time after which a woman has experienced 12 consecutive months of 
amenorrhea (lack of menstruation). 
4.2 RECRUITMENT STRATEGIES 
Participants will be selected through IRB approved generic recruitment advertisements which are specifically 
designed to recruit participants into the volunteer database for future smoking and tobacco use related research 
at the Rose Research Center. For this database, many of the participants have provided basic smoking history 
data along with demographic information, which will allow selection of potentially interested participants. 
Participants who call in will be screened into the volunteer database, and if they pre-qualify, will be offered the 
option to prescreen for this protocol. 
Participants will be contacted only with IRB approved appropriate materials and information submitted along 
with this protocol. These documents will include a brief description of the study and information on how to 
prescreen for participation. Participants will be contacted by phone, email and text message prompting 
interested participants to prescreen through an electronic screen form. 


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4.2.1 
Pre-Screening 
Pre-screening will be completed prior to V1 for all participants. Participants will be provided with a set of IRB 
approved questions directly related to the inclusion and exclusion criteria. Based upon the outcome of these 
questions, potential participants may be scheduled for a screening visit (V1). 
4.3 PARTICIPANT RETENTION IN THE STUDY 
All candidates who schedule a screening visit (V1) will receive a series of email, text, and telephone reminders; 
participants are also permitted through these communications to confirm, cancel, or reschedule all their 
appointments. 
4.4 DISCONTINUATION OF PARTICIPANTS FROM STUDY 
Discontinued participants will include both participants who withdraw from the study (participant’s decision) or 
participants who are discontinued from the study (following Investigator’s decision). A participant can only be 
discontinued from the study after enrollment. Participants that are not enrolled are considered screen failures. 
Participants will be informed that they are free to withdraw from the study at any time. Participants should be 
questioned for the reason of premature withdrawal from the study, although they are not obliged to disclose it.  
Participants discontinued from the study cannot re-enter the study.  
4.4.1 
Participants must be discontinued from the study for any of the following reasons: 
• No-show to appointments and unable to reschedule within the visit window. 
• Withdrawal of informed consent. 
• Any adverse effect or condition that would jeopardize continued safe study participation. 
• Pregnancy test is positive.  
• Discontinuation is considered to be in the best interest for the participant or for other participants 
participating to the study, as judged by the Investigator or designee. 
4.5 LOST TO FOLLOW-UP 
A reasonable number of attempts to contact the participant (including written correspondence and phone calls) 
should be made and documented in the source documents. The date of the last contact (e.g. last visit, last 
phone call) should also be recorded in the source document. When the PI(s) or designee(s) declare(s) a 
participant is lost to follow-up, the lost to follow-up date will be recorded and will correspond to the date of the 
end of study (EOS) of the participant.  
4.6 VIOLATION OF INCLUSION/EXCLUSION CRITERIA 
Participants who, after signing the ICF, do not meet the inclusion and exclusion criteria will not be enrolled in 
the study and will be considered screen failures. Re-screening for the study is not permitted. 
4.7 PARTICIPANT COMPENSATION 
There will be a payment of $25 for the screening session, $50 for Visit 2 through Visit 6, and $100 for Visit 7. 
Participants will also receive payments of $5/day for responding to daily text messages. 


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If participants are asked by study staff to return to the Center to complete or redo parts of the sessions in 
situations of equipment malfunctions or other circumstances that are beyond the participants’ control, 
participants may be reimbursed for mileage (based on the IRS’s mileage rate). 
Participants who decide to withdraw from the study will be paid for the part of the study they have completed.  
4.8 SESSION AND RESPONSE WINDOWS 
4.8.1 
V2 Session Window 
Participants may attend V2 up to 30 days post Screening Session (V1).  
4.8.2 
All other visit Windows 
Participants may attend sessions up to four-calendar day’s pre or post the scheduled visit. 
4.8.3 
SMS Response Window 
The SMS response window will be open until the next SMS message is sent.  
 HYDROXYZINE 
5.1 DESCRIPTION OF HYDROXYZINE 
Hydroxyzine is an FDA approved first-generation antihistamine of the diphenylmethane and piperazine class that 
has antiemetic, anxiolytic, and sedative effects. Hydroxyzine’s effects are primarily derived due to its actions as a 
potent H1 receptor inverse agonist. It also acts as an antagonist on the 5-HT2A, D2, and α1-adrenergic 
receptors. Because of its antiserotonergic effects, as well as the antagonistic effects on multiple receptor 
systems in the brain, hydroxyzine is noted to have strong anxiolytic properties, as well as mild antiobsessive and 
antipsychotic properties. Even with its effective sedative, hypnotic, and anxiolytic effects, hydroxyzine does not 
demonstrate any of the abuse, dependence, addiction or toxicity potential associated with medications within 
the same therapeutic range (such as benzodiazepines or nonbenzodiazepine hypnotics).13  
LLorca et al. demonstrated the safety and efficacy of hydroxyzine in the treatment of generalized anxiety 
disorder.20 A common adverse event for hydroxyzine (occurring 10% or more) is drowsiness. All other adverse 
events occurred less than 10% or were of unknown incidence. This includes dry mouth, cough, unusual 
tiredness, and irregular or slow heart rate.21 
A Cochrane Review from 2014 which looked at interventions for nausea and vomiting in early pregnancy noted 
that hydroxyzine had a statistically significant improvement in nausea at a dose of 25 mg twice a day, when 
compared with placebo (see figure 2).24 It also noted that only 7% of the participants using hydroxyzine reported 
only “slight drowsiness” while taking this medication at this particular dose.24 No other adverse effects were 
reported in this review. 


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Figure 2: From Matthews A, Haas DM, O’Mathúna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. Cochrane 
Database Syst Rev. 2015;(9):CD007575. doi:10.1002/14651858.CD007575.pub4 
A study published in 2012 evaluated the efficacy of combining hydroxyzine with ondansetron for treatment of 
side effects associated with chemotherapy regiments which utilized highly emetogenic drugs. This study 
demonstrated that complete control of acute emesis was achieved in 56% of pediatric cancer patients utilizing 
both antiemetic medications versus only 22% utilizing ondansetron without hydroxyzine (p=0.006).25 This study 
also reported that patients and parents noted “…significantly better sleeping quality, appetite, activity and 
mood…” for those patients taking ondansetron with hydroxyzine versus without hydroxyzine. The dose of 
hydroxyzine used was 1 mg/kg/dose, equivalent to 77 mg for an average adult female and 89 mg for an average 
adult male (an average American female weighs 170 lbs. and an average American male weighs 197 lbs. 
according to the CDC).26 Dosing for this study will be based on minimizing the risk of sedation (25 mg AM dosing) 
while optimizing the beneficial effects of the study drug (50 mg PM dosing). Participants will be titrated to these 
doses in a similar fashion as the titration of varenicline, allowing for dose adjustment based on daily evaluation 
of potential side effects. 
5.2 HYDROXYZINE PRODUCT USE TIMEFRAME 
Dosing will begin one week before a target quit-smoking date and will continue for a total of approximately 12 
weeks, the same duration as the FDA-approved dosing for varenicline. Since hydroxyzine does not demonstrate 
any dependence or addictive properties, there is no indication to taper the dose.  
5.3 DOSAGE 
• First 3 days of treatment: PM – two 25 mg tablet orally.  
• Starting on the fourth day of treatment and continuing until the EOS: AM – one 25 mg tablet orally; PM 
– two 25 mg tablets orally. 
• Dosing will be adjusted based on reported side effects. 


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5.4 DOSE ADJUSTMENT PROCEDURES 
Dose adjustments for hydroxyzine will be performed by licensed medical providers based on adverse effects 
reported by participants (e.g. daytime sedation…stop the AM dose of hydroxyzine, difficulty waking in the 
am…decrease nighttime dose of hydroxyzine). Participants will be contacted with a follow-up call by Research 
Medical Staff within 72 hours of any dose adjustment. 
5.5 ACCOUNTABILITY AND COMPLIANCE 
5.5.1 
Dispensing Product 
The hydroxyzine will be dispensed by the Investigator or designated study staff utilizing blister-pack technology 
to enhance compliance and accountability. Each dispense and collection of the product will be recorded during 
each laboratory visit (Visit 2 through Visit 6). All study-related drugs will be expected to be returned by the 
participant at the End-Of-Study (Visit 7 or early termination). 
Prior to dispensing, the site will ensure that the product packaging is labelled with the protocol number and 
unique participant identifiers, date it was dispensed, and the statements “For investigational use only” and 
“Keep out of reach of children”. 
5.5.2 
Storage and Accountability 
Hydroxyzine will be stored in a climate-controlled secured-storage site (15 degrees C to 30 degrees C) with 
access limited to authorized personnel only. Full accountability of the distributed products will be ensured by 
designated staff.  
5.5.3 
Compliance 
Compliance will be ensured by strict distribution of the product, daily SMS messages, and collection of unused 
products at each study session. This information will be documented in appropriate logs.  
 VARENICLINE 
6.1 DESCRIPTION OF VARENICLINE 
Varenicline is one of two FDA-approved non-nicotine medications prescribed as a smoking cessation aid. It is a 
partial agonist of the α4β2 nACHR. Due to its relatively long half-life, compared to nicotine, varenicline also acts 
as an antagonist, blocking occupied receptors from additional stimulation from nicotine. Recognized as one of 
the most effective monotherapy treatments for tobacco dependence, the medication increases the odds of 
quitting smoking by nearly fourfold compared with placebo. Hays et al. found varenicline to be generally safe 
and well tolerated as a smoking cessation aid. Common adverse events associated with varenicline (occurring 
10% or more) include nausea, insomnia, abnormal dreams, headaches, and nasopharyngitis.19 Nausea, the most 
common side effect of varenicline, has been reported as high as 30%. Abnormal dreams and insomnia have been 
reported by over 10% of users.27–29 
6.2 DOSAGE 
• 0.5 mg tablet orally once a day for 3 days. 
• Starting on the fourth day, 0.5 mg tablet twice a day, orally. 


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• After one week, 1.0 mg tablet twice a day, orally. 
6.3 DOSE ADJUSTMENT PROCEDURES 
Dose adjustments for varenicline will be performed by licensed medical providers based on adverse effects 
reported by participants (e.g. insomnia, abnormal dreams, mood disturbances, anxiety…decrease dose to 0.5 mg 
twice a day for moderate to severe side effects). Participants will be contacted with a follow-up call by Research 
Medical Staff within 72 hours of any dose adjustment. 
6.4 ACCOUNTABILITY AND COMPLIANCE 
6.4.1 
Dispensing Product 
The varenicline will be dispensed by the Investigator or designated study staff utilizing blister-pack technology to 
enhance compliance and accountability. Each dispense and collection of the product will be recorded during 
each laboratory visit (Visit 2 through Visit 6). All study-related drug will be collected at the End-Of-Study (Visit 7 
or early termination). 
Prior to dispensing, the site will ensure that the product packaging is labelled with the protocol number and 
unique participant identifiers, date it was dispensed, and the statements “For investigational use only” and 
“Keep out of reach of children”. 
6.4.2 
Storage and Accountability 
Varenicline will be stored in a climate-controlled secured-storage site with access limited to the authorized 
personnel only. Full accountability of the distributed products will be ensured by designated staff.  
6.4.3 
Compliance 
Compliance will be ensured by strict distribution of the product, daily SMS messages, and collection of unused 
products at each study session. This information will be documented in appropriate logs.  
 STUDY PROCEDURES AND ACTIVITIES 
Personnel performing study assessments must have appropriate and documented training. An overview of all 
study assessments is shown in the schedule of events (Section 8.5). Study personnel will adhere to standard 
operating procedures (SOPs) for all activities. Appropriate medical advice will be provided to the participant in 
case of any medical findings requiring health care. 
7.1 INFORMED CONSENT AND GUIDANCE 
Prior to any study assessments being performed, the participant will be asked to provide their written consent 
to participate in the study on an informed consent form (ICF). All assessments must start after the time of ICF 
signature by the participant. 
Designated staff will obtain written consent from each participant under the supervision of the Principal 
Investigator. The person obtaining consent provides the participants with a written document explaining the 
procedures and risks and will answer any questions. A signed copy of the informed consent form will be given to 


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each participant. Participants are informed that they may withdraw from participation in the study at any time 
without penalty.  
Because of the nature of this study and the number of questionnaires that participants are expected to 
complete, we do not recruit potential participants who do not read, are blind or who do not read/understand 
English. We are not equipped to validate alternate versions of our questionnaires. Questionnaires cannot be 
administered orally by a translator or by technicians to illiterate or blind participants because the data obtained 
would not be comparable to self-administered questionnaires. 
7.2 SAFETY LABORATORY AND OTHER ASSESSMENTS 
An overview of all assessments is provided in the schedule of events (Section 8.5). 
Non-fasting blood samples and urine samples will be collected by qualified and trained site personnel. 
Participants will be in a seated or in a supine position during blood collection. 
The maximal total volume of blood drawn for each participant will be 12.5 ml for clinical chemistry, hematology, 
and serum pregnancy (for females only). 
Samples for clinical chemistry, hematology, urinalysis, and serum pregnancy test will be sent to a central 
laboratory for analysis. Urine pregnancy and urine drug testing will be performed on-site. 
The results of the clinical chemistry, hematology and urinalysis safety panel will not routinely be given to 
participants. However, if the participant’s laboratory results are clinically relevant (including positive pregnancy 
tests), the medical staff will send the participant a copy of the laboratory results. Participants who are accepted 
into the study but need medical follow up due to minor abnormalities in laboratory results will also receive a 
copy of the laboratory results. 
7.2.1 
Blood Samples 
Blood samples will be collected by qualified and trained site personnel. Participants should be in a seated or 
supine position during blood collection.  
The maximal total volume of blood drawn for each participant will be around 12.5 mL for safety analysis. 
Samples will be sent to an external laboratory for testing.   
Hematology 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration (MCHC) 
Hematocrit 
Red blood cell (RBC) count 
Differential WBC count 
Platelet count 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
White blood cell (WBC) count 
 
Clinical Chemistry 
Sodium  
Potassium 


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Chloride 
Carbon Dioxide 
Blood Urea Nitrogen 
Creatinine 
Glucose 
Total Protein 
Albumin 
Total Bilirubin 
Alkaline Phosphatase 
Alanine aminotransferase (ALT) 
Estimated Glomerular Filtration Rate 
Aspartate aminotransferase (AST) 
Calcium  
 
Table 1 - Clinical Chemistry & Hematology Assessments 
7.2.2 
Serum Pregnancy Test 
Serum pregnancy test will only be performed during the screening visit for all female participants 
Serum Pregnancy Test 
Qualitative human chorionic gonadotropin (HCG) test 
Table 2 – Serum Pregnancy Test 
7.2.3 
Urine Samples 
Urine samples will be collected for the urine drug screen (at screening session), urine pregnancy test (at all 
sessions except screening), and safety urinalysis (at screening session). The urine drug screen and pregnancy 
tests will be performed by study personnel at the study site. The urine sample collected for urinalysis will be 
sent to an external laboratory for testing. 
In case of any positive pregnancy test, the Investigator or designee will inform the participant about the risks 
associated with smoking during pregnancy. 
Urinalysis 
pH 
Red blood cell traces 
Bilirubin 
Protein 
Glucose 
Specific gravity 
Nitrite 
WBC Esterase 
Table 3 - Urinalysis Assessments 
Drug Screening 
Amphetamine 
Cocaine 
THC 
Methamphetamine 
Opiates 
Table 4 - Drug Screening 
7.2.4 
Urine Pregnancy Test 
The urine pregnancy tests will be performed by study personnel at RRC. Urine pregnancy tests will be performed 
for all females at all visits except screening. 


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7.2.5 
Expired Air CO Breath Test 
Carbon Monoxide (CO) in participant’s exhaled breath (expressed as ppm) will be measured using a Vitalograph 
CO Monitor. Participants must have an expired air CO reading at V1 of at least 10 ppm for inclusion into this 
study. This test will be repeated at each of the laboratory sessions. 
7.2.6 
Medical History and Concomitant Disease 
Relevant medical history and concomitant disease will be documented at the screening visit (V1). Medical 
history is defined as any condition that started and ended prior to V1. A concomitant disease is defined as any 
condition that started prior to V1 and is still ongoing at V1 (this may also include findings detected during the 
screening visit). 
7.2.7 
Prior and Concomitant Medication 
All medication taken four weeks prior to the screening visit (V1) and during the study will be documented using 
a source document. Medications which are stopped before V1 will be considered as prior medication. 
Medication which was started prior to V1 and which is still being taken by the participant during the study as 
well as medication that is initiated after V1 will be considered as a concomitant medication. This applies to both 
prescription and over-the-counter products (e.g., vitamins). 
Records of prior and concomitant medications taken include the drug name (preferably both generic and trade 
name), route of administration, dose/unit, frequency of use, indication, the start and if applicable, the stop date. 
Any therapy changes (including changes of regimen) during the study will be documented. 
The questionnaires will be administered to the participants using paper questionnaires and/or an electronic data 
collection system. The timing of these questionnaires is outlined in the Schedule of Events 8.5.  
7.2.8 
Demographics 
Sex, date of birth, race and ethnicity will be recorded for each participant according to Section 8.5. 
7.2.9 
Height and Weight 
Height and weight will be measured and recorded according to Section 8.5.  
7.2.10 Physical Examination 
A physical examination will be performed according to Section 8.5. The physical examination will include review 
of general appearance, hair and skin, head, eyes, ears, nose and throat, neck, chest, abdomen, dentition, 
cardiovascular, musculoskeletal and neurological systems. The physical examination is to be conducted by a 
designated fully trained and licensed medical staff. 
Appropriate medical advice will be provided to the participant if any medical findings requiring health care are 
identified. 
7.2.11 AE/SAE Reporting 
AEs/SAEs will be assessed using questionnaires and face-to-face interviews at the indicated time points and 
spontaneous reporting from the time of ICF signature until the EOS for the participant (see Section 8.5). 
7.2.12 Electrocardiogram (ECG) 
ECG recording will be performed as per RRC Standard Operating Procedures at screening. A standard 12-lead 
ECG will be recorded after the participant has rested for at least 5 minutes in a supine position.  


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The following parameters will be documented: heart rate, PR interval, QRS interval, QT interval, and QTc interval 
(Bazett). Every ECG will be assessed as normal, abnormal – not clinically significant, or abnormal – clinically 
significant. 
ECG printouts will be interpreted by a qualified physician or physician assistant. Any printouts of ECGs on 
thermo-sensitive paper will be photocopied and stapled together for inclusion in the source documents and 
signed by the qualified physician or physician assistant.  
7.2.13 Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate and respiratory rate), will be measured in sitting 
position after the participant has rested for at least 5 minutes according to Section 8.5. At the screening visit, 
blood pressure and heart rate will be measured again at least two minutes later in a standing position.  
7.2.14 Questionnaires 
The questionnaires will be administered to the participants using paper questionnaires and/or an electronic data 
collection system. The questionnaires will be asked according to Section 8.5. 
 10-Item Perceived Stress Scale (PSS-10) 
Self-report questionnaires are the simplest method for obtaining a rapid evaluation of a participant’s realized 
stress levels. The Perceived Stress Scale (PSS) was developed in 1983 as a psychometrically valid measure of 
perceived stress. A 2011 study reviewed the use of the PSS in a sample of participants who smoked, evaluating 
three different versions; the PSS-14 (14-item questionnaire), the PSS-10 (10-item questionnaire), and the PSS-4 
(4-item questionnaire). The results from this 2011 study confirmed the psychometric properties of all three 
versions.30 Our study will utilize the PSS-10 during all visits after enrollment (V2 through V7) to evaluate self-
reported perceived stress levels.  
 6-Item State-Trait Inventory (STAI) 
In 2011, Dr. Laura Julian from University of California, San Francisco, published a review of available validated 
methods for accurately measuring anxiety. Her review focused on self-reported measures of general anxiety. 
She reviewed three different models; the State-Trait Anxiety Index, the Beck Anxiety Inventory, and the anxiety 
subscale of the Hospital Anxiety and Depression Scale. The STAI demonstrated excellent reliability and good 
validity, and is both responsive and sensitive to change.31,32 The STAI is among the most widely used measures of 
general anxiety. Our study will utilize the 6-item STAI during all visits after enrollment (V2 through V7) to 
evaluate self-reported anxiety levels. 
 PHQ-9 -- The Patient Health Questionnaire 
The Patient Health Questionnaire PHQ-9 for Depression will be used to screen for current (within 2 weeks) 
depression. Potential participants who score >9 (or who score >0 on item #9 (“Thoughts that you would be 
better off dead, or of hurting yourself in some way”)) will be excluded from study participation, and, at the 
discretion of the study physician/physician assistants, referred to appropriate psychiatric treatment. Participants 
will respond to this questionnaire at all visits. This questionnaire will be administered at every visit, including the 
screening visit (V1 through V7). 
 Modified Cigarette Evaluation Questionnaire (mCEQ) 
The mCEQ assesses the degree to which participants experience the reinforcing effects of smoking. This 
questionnaire will be administered after enrollment and prior to commencing the investigational products (V2 
and V3). 


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 MNWS –Minnesota Nicotine Withdrawal Scale 
The MNWS will be used at all visits after “quit day” (V4 through V7) to assess nicotine withdrawal symptoms 
including craving and mood effects. Participants will be asked to assess the following seven symptoms (on a 
5-point scale ranging from 0 to 4, where 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe): 
• 
Desire or craving to smoke 
• 
Anger, irritability, frustration 
• 
Anxiety or nervousness 
• 
Difficulty of concentrating 
• 
Impatience, restlessness 
• 
Hunger 
• 
Depression 
 FTND -- The Fagerström Test for Nicotine Dependence 
The Fagerström Test for Nicotine Dependence is a six-item questionnaire developed by Karl-Olov Fagerström 
and is used to determine someone’s level of nicotine dependence. The scores obtained on the test allow the 
classification of nicotine dependence in three different levels: mild (0-3 points), moderate (4-6 points), and 
severe (7 -10 points). This questionnaire will be given at all visits (V1 through V7). 
 WI-PREPARE – Wisconsin Predicting Patients’ Relapse Questionnaire 
The WI-PREPARE is a seven-item questionnaire that is designed to assess a participant’s susceptibility to smoking 
relapse. The questionnaire includes measures of physical dependency, environmental factors and smoking 
characteristics. Participants will respond to this questionnaire after enrollment and prior to the selected “quit 
day” (V2 and V3). 
 Prior and Concomitant Medication 
At each visit, participants will report any changes in medication use, including the use of supplements, vitamins, 
over-the-counter medications, and prescription medications.  
 Smoking History Questionnaire 
The Smoking History is a questionnaire designed to help assess the participant’s current and past smoking 
habits. This questionnaire will be administered at screening (V1) and  will include questions about the number of 
years participants have smoked combustible cigarettes (CC), the number of CCs per day smoked over the last 12 
months, brand of CCs, use of other tobacco products and use of nicotine replacement therapy or other smoking 
cessation treatments. This questionnaire will also be used to check eligibility criteria. 
 Registration Form 
This form is an internal questionnaire designed to collect demographic information about participants. It will be 
administered at screening (V1). 
 Medical History Form 
The Medical History form is an internal questionnaire designed to help assess the participant’s current health 
and any health history. This questionnaire also includes questions about all medications (include prescription 
medications, other-the-counter medications or supplements) taken in the past 30 days. It is designed to help 
assess the participant’s current health and health history and is used to help determine eligibility. This form is 
administered at the initial screening visit (V1). 


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 Review of Systems 
The Review of Systems is an internal questionnaire administered at screening (V1) to help assess the 
participant’s current health and health history by asking about the presence of a list of symptoms. 
 Employment History 
The Employment History is an internal questionnaire designed to collect information about a participants’ social 
economic status. Participants will be presented this questionnaire after enrollment, at the second visit (V2). 
 Adverse Effects 
During each visit after enrollment (V2 through V7), participants will respond to adverse events based on a 
mild/moderate/severe rating. The questionnaire will use both targeted questions and open-ended questions to 
access for any adverse effects/events. Participants will respond to SMS text message inquiries for study specific 
adverse effects, on a daily basis, commencing after enrollment (see Section 8.8). 
 Medication Compliance 
Participants will be queried via SMS text messages whether they have been compliant with taking the study 
specific medications. These messages will commence after the second visit and continue through the End of 
Study (see Section 8.8). 
 Smoking Status 
 SMS text messages will be sent to participants starting after enrollment, through the End of Study, to ascertain 
the participants smoking status (see Section 8.8). 
 SESSIONS 
8.1 SCREENING SESSION (V1) 
Eligibility of participants to participate in this study will be assessed at the screening visit (V1). The ICF will be 
signed, dated and timed prior to any other screening procedures (see Section 8.5). 
The sequence of the following assessments will be at the discretion of the Investigator (or designee) after 
signature of the ICF. 
• 
Questionnaires 
o Smoking History 
o Registration Form 
o Medical History (with Review of Systems) 
o Patient Health Questionnaire (PHQ-9) 
• 
Prior and Concomitant Medication 
• 
Expired air CO breath test  
• 
Urine collection for urinalysis and drug screen 
• 
Vital signs (blood pressure, heart rate, respiratory rate) 
• 
Height and weight / BMI 
• 
Temperature 
• 
Electrocardiogram (ECG) 
• 
Physical examination  


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• 
Blood collection for safety laboratory testing (including pregnancy test for females) 
• 
Instructions on use of the SMS messaging/questionnaire system 
8.2 5-DAY OBSERVATION PERIOD 
After verification of eligibility (approximately two days after screening), participants will be enrolled in the study 
and commence a five-day observational period. Participants will be called and given instructions on the use of 
the SMS system which will administer questions about adverse effects and smoking status in order to collect 
baseline data prior to start of the study drugs. 
8.3 PRE-QUIT SESSION (V2) 
After completion of a minimum five-day observational period, participants will come to the Center for 
assessment, training (including brief quit smoking counseling), and dispensing of study drugs. The quit date will 
be scheduled for the day after Visit 3, and seven days after commencing the study drugs. The sequence of the 
following assessments will be at the discretion of the Investigator or designee. 
• 
Document concomitant disease and medication changes 
• 
Physical examination (if indicated) 
• 
Expired air CO breath test  
• 
Vital signs (blood pressure, heart rate, respiratory rate)  
• 
Weight 
• 
Brief smoking cessation counseling (QuitAssist Counseling Handout) 
• 
Urine pregnancy test (all females) 
• 
Dispensing of study drugs 
• 
Verification of proper use of the SMS messaging (refresher training, if needed) 
• 
Questionnaires 
o Employment History 
o FTND  
o PSS-10 
o 6-Item STAI 
o Adverse Effects Questionnaire  
o Patient Health Questionnaire (PHQ-9) 
o Wisconsin-Predicting Patient’s Relapse (WI-PREPARE) 
o Modified Cigarette Evaluation Questionnaire (mCEQ) 
o Smoking Status (daily via SMS survey, commence after visit) 
o Medication Compliance (daily via SMS survey, commence after visit) 
8.4 DAY BEFORE QUIT DATE (V3) 
Six days after starting medications (one day prior to quit date), participants will return to the Center for 
assessment and collection/dispensing of study drugs. The sequence of the following assessments will be at the 
discretion of the Investigator or designee. 
• 
Document concomitant disease and medication changes 
• 
Physical examination (if indicated) 


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• 
Expired air CO breath test  
• 
Vital signs (blood pressure, heart rate, respiratory rate)  
• 
Weight  
• 
Brief review of smoking cessation counseling (if indicated) 
• 
Urine pregnancy test (all females) 
• 
Collection and dispensing of study drugs 
• 
Assess medication compliance 
• 
Verification of proper use of the SMS messaging (refresher training, if needed) 
• 
Questionnaires 
o FTND  
o PSS-10 
o 6-Item STAI 
o Adverse Effects Questionnaire 
o Patient Health Questionnaire (PHQ-9) 
o Wisconsin-Predicting Patient’s Relapse (WI-PREPARE) 
o Modified Cigarette Evaluation Questionnaire (mCEQ) 
o Smoking Status (review with participant and continue daily via SMS survey) 
o Medication Compliance (review with participant and continue daily via SMS survey) 
8.5 POST-QUIT SESSIONS (V4-V7) 
Sessions scheduled after the quit-smoking date will be conducted at 2 weeks after the quit date and then at 4-
week intervals until the end of the 12-week treatment period. The sequence of the following assessments will 
be at the discretion of the Investigator or designee. 
• 
Document concomitant disease and medication changes 
• 
Physical examination (if indicated) 
• 
Expired air CO breath test  
• 
Vital signs (blood pressure, heart rate, respiratory rate)  
• 
Weight  
• 
Brief review of smoking cessation counseling (if indicated) 
• 
Urine pregnancy test (all females) 
• 
Collection and dispensing of study drugs (collection only at the EOS visit) 
• 
Assess medication compliance 
• 
Verification of proper use of the SMS messaging (refresher training, if needed) 
• 
Questionnaires 
o FTND  
o PSS-10 
o MNWS 
o 6-Item STAI 
o Adverse Effects Questionnaire 
o Patient Health Questionnaire (PHQ-9) 
o Smoking Status (review with participant and continue daily via SMS survey until End of Study) 
o Medication Compliance (review with participant and continue daily via SMS survey until End of 
Study) 


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8.6 6-MONTH FOLLOW UP 
Participants who successfully complete the study and are abstinent at the final visit (V7), will be contacted six 
months after the quit day utilizing an automated SMS messaging system, to ascertain their current smoking 
status. 
 
8.7 SCHEDULE OF EVENTS 
Visit Assessments and Procedures 
Screening 
Session 
5-day 
observation 
period 
Laboratory Sessions 
 
 
 
6-month 
f/u 
V1 
  
V2 
V3 
V4 
V5 
V6 
V7 
 
Informed Consent and Guidance 
• 
  
  
  
  
  
  
  
 
Inclusion/Exclusion Criteria 
• 
  
  
  
  
  
  
  
 
Enrollment 
  
•* 
  
  
  
  
  
  
 
Prior and Concomitant Medication 
• 
  
• 
• 
• 
• 
• 
• 
 
Questionnaires 
Smoking History Questionnaire 
• 
  
  
  
  
  
  
  
 
Registration Form 
• 
  
  
  
  
  
  
  
 
Employment History 
  
  
• 
  
  
  
  
  
 
Medical History/Review of Systems 
• 
  
  
  
  
  
  
  
 
10-item Perceived Stress Scale (PSS-10) 
 
  
• 
• 
• 
• 
• 
• 
 
6-Item State-Trait Inventory 
 
  
• 
• 
• 
• 
• 
• 
 
Wisconsin-Predicting Patient's Relapse (WI-PREPARE) 
 
  
• 
 • 
  
  
  
  
 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
 
 
• 
• 
 
 
 
 
 
The Fagerström Test for Nicotine Dependence (FTND) 
 
  
• 
• 
• 
• 
• 
• 
 
Patient Health Questionnaire (PHQ-9) 
• 
  
• 
• 
• 
• 
• 
• 
 
Minnesota Nicotine Withdrawal Scale (MNWS) 
  
  
 
 
• 
• 
• 
• 
 
Smoking Status (via daily SMS text) 
  
• 
• 
• 
• 
• 
• 
• 
• 
Medication Compliance (via daily SMS text) 
  
  
• 
• 
• 
• 
• 
• 
 
Adverse Effects Questionnaire (at visits and daily SMS Text) 
 
• 
• 
• 
• 
• 
• 
• 
 
Safety Laboratories 
• 
  
  
  
  
  
  
  
 
Serum Pregnancy Test (Females) 
• 
  
  
  
  
  
  
  
 
Urine Pregnancy Test (Females) 
  
  
• 
• 
• 
• 
• 
• 
 
Urine Drug Screen 
• 
  
  
  
  
  
  
  
 
CO Breath Test 
• 
  
• 
• 
• 
• 
• 
• 
 
ECG 
• 
  
  
  
  
  
  
  
 
Vitals 
Blood Pressure 
• 
  
• 
• 
• 
• 
• 
• 
 
Heart rate 
• 
  
• 
• 
• 
• 
• 
• 
 
Temperature 
• 
  
  
  
  
  
  
  
 
Respiratory rate 
• 
  
• 
• 
• 
• 
• 
• 
 
Weight 
• 
  
• 
• 
• 
• 
• 
• 
 
Height 
• 
  
  
  
  
  
  
  
 
BMI 
• 
 
 
 
 
 
 
 
 
Physical Examination 
• 
  
•# 
•# 
•# 
•# 
•# 
•# 
 
Collect Used/Unused Blister Packs 
  
  
  
• 
• 
• 
• 
• 
 
Dispense Study Drugs in Blister Packs 
  
  
• 
• 
• 
• 
• 
  
 
  
*After evaluation of safety labs, prior to start of observational period 
  
 
# Targeted examination as needed 
 
 


8.8 SMS MESSAGING 
8.8.1 
Daily SMS Message (after enrollment, prior to V2) – Participants will receive a text with a link to a 
survey to access the following: 
• How soon after you wake up did you smoke your first cigarette? 
1-Within 5 Minutes, 2-6 to 30 Minutes, 3-31 to 60 Minutes, 4-After 60 Minutes 
• How many cigarettes did you smoke today? 
• What was your level of stress today?  
1-No Stress, 2-Mild Stress, 3-Moderate Stress, 4-A Lot of Stress, 5-Extreme Stress 
• How well did you sleep last night? 
1-No problems, 2-Mild problems, 3-Moderate problems, 4-A Lot of problems, 5-Extreme 
problems 
• Did you feel nauseated today? 
1-No nausea, 2-Mild nausea, 3-Moderate nausea, 4-A lot of nausea, 5-Extreme nausea 
8.8.2 
Daily SMS Message (after Visit 2) -- Participants will receive a text with a link to a survey to assess 
the following: 
• Have you smoked any cigarettes today? 
o If yes, how soon after you wake up did you smoke your first cigarette? 
1-Within 5 Minutes, 2-6 to 30 Minutes, 3-31 to 60 Minutes, 4-After 60 Minutes  
o How many cigarettes did you smoke today? 
• Did you take your study drugs this morning? 
• Did you take your study drugs this evening? 
• What was your level of stress today?  
1-No Stress, 2-Mild Stress, 3-Moderate Stress, 4-A Lot of Stress, 5-Extreme Stress 
• How well did you sleep last night? 
1-No problems, 2-Mild problems, 3-Moderate problems, 4-A Lot of problems, 5-Extreme 
problems 
• Did you feel nauseated today? 
1-No nausea, 2-Mild nausea, 3-Moderate nausea, 4-A lot of nausea, 5-Extreme nausea 
8.8.3 
6-Month follow up SMS Message -- Participants will receive a text with a link to a survey to assess 
the following: 
• Have you smoked a cigarette since your last visit? 
o If yes, are you still smoking cigarettes right now? 
 RISK / BENEFIT INFORMATION 
9.1 POTENTIAL BENEFITS 
The participants will be encouraged to quit smoking, which would significantly reduce their risk of 
smoking-related diseases. 


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9.2 IMPORTANCE OF KNOWLEDGE TO BE GAINED 
By conducting the proposed research, we may develop a new approach to smoking cessation treatment 
that promises to help a significantly larger proportion of smokers to quit successfully. This would have a 
major positive impact on public health. 
9.3 POTENTIAL RISKS 
Continuing to smoke carries significant health risks; if participants are successful at maintaining 
abstinence (and possibly quit), the participants in the studies will realize a significant improvement in 
their health and a decrease in their risk of morbidity and mortality associated with smoking combustible 
cigarettes.  
9.3.1 
Hydroxyzine 
Hydroxyzine is a first-generation antihistamine which has FDA-approval as an antiemetic, anxiolytic, and 
sedative medication. Even with its effective sedative, hypnotic, and anxiolytic effects, hydroxyzine does 
not demonstrate any of the abuse, dependence, addiction or toxicity potential associated with 
medications within the same therapeutic range (such as benzodiazepines or nonbenzodiazepine 
hypnotics).13 A common adverse event for hydroxyzine (occurring 10% or more) is drowsiness. All other 
adverse events occurred less than 10% or were of unknown incidence. This includes dry mouth, cough, 
unusual tiredness, and irregular or slow heart rate.21 Studies of hydroxyzine have shown a lack of organ 
toxicity and absence of dependence. Case reports of QT prolongation and Torsade de Pointes have been 
reported during post-marketing analysis. These reports were noted to occur in patients with other risk 
factors for QT prolongation. 
9.3.2 
Varenicline 
Varenicline is one of the most widely used prescription medications for smoking cessation. Common 
adverse events associated with varenicline include nausea, insomnia, abnormal dreams, headaches, and 
nasopharyngitis.19 The most common adverse reaction reported is nausea, with 30-40% of participants 
in randomized control trials reporting mild to moderate levels of nausea.33 Discontinuation/drop-out 
rates of nearly 10% have been noted during clinical trials due to these adverse effects.34 In addition to 
the potential drug-specific side effects noted, any medication may trigger a serious allergic reaction and 
may cause shock, seizures (convulsions, epilepsy, "fits"), loss of consciousness, tingling, swelling of the 
face, lips, tongue, throat and/or vocal cords, difficulty breathing, asthma, wheezing, rash, hives, itching, 
and possibly death. 
9.3.3 
Nicotine Withdrawal 
Participants may experience nicotine withdrawal symptoms, including craving, difficulty concentrating, 
nausea, insomnia, headache, mood disturbance and increased appetite/weight gain. 
9.3.4 
Blood Draw 
The risks associated with venipuncture are minimal and include momentary discomfort and/or bruising. 
Infection, excess bleeding, clotting, and fainting are also possible, although unlikely. 


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9.4 PROTECTION AGAINST RISKS 
Participants will be screened medically and monitored throughout the study. Participants will be 
instructed to report any side effects to study staff, who will communicate these reports immediately to 
the medical staff. The most appropriate course of action will be determined, which may include options 
for dose reduction or termination of treatment. Participants whose treatment is terminated will be 
encouraged to remain in the study for assessment of outcomes and to receive continuing social support 
for quitting smoking. Participants will, however, be reminded that they have the option to withdraw 
from the study at any time. Participants will also be given the 24-hour emergency contact number in the 
event that side effects or adverse events occur between sessions. 
9.4.1 
Blood Pressure Monitoring 
After study enrollment, if blood pressure during laboratory visits is above 160/100, then the following 
actions will be taken to enhance participant safety:  
• If BP >210/120 with symptoms of malignant hypertension, all experimental interventions will 
be stopped immediately, and the participant will be referred to appropriate medical 
treatment. Participation may resume, with continued monitoring, if BP is no greater than 
150/100.  
• If BP > 160/100 for 2 consecutive sessions, the Center will request that the participant have 
their BP checked weekly by their PCP, local pharmacy, or home machine and call us with 
results. Participants will also be encouraged to see their PCP regarding evaluation, treatment, 
and further monitoring. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 TRAINING OF STAFF 
The Investigator or designee will ensure that appropriate training relevant to the study is provided to all 
staff involved in the study, and that any new information relevant to the performance of this study is 
forwarded in a timely manner to the staff.  
10.2 AUDITS AND INSPECTIONS 
Good Clinical Practice regulations require independent inspections of clinical program activities. Such 
inspections may be performed at any time before, during, and after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed and accurately reported, according to the 
protocol, ICH/GCP guidelines and any applicable regulatory requirements. The Investigator or designee 
will contact the Sponsor immediately if contacted by a regulatory agency about an inspection at their 
site. 


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The Investigator and study staff are responsible for maintaining a comprehensive and accurate filing 
system of all study-related documentation that will be suitable for inspection at any time by the 
Sponsor, its authorized representative, and other regulatory agencies.  
 REPORTING OF ADVERSE EVENTS 
11.1 DEFINITIONS 
11.1.1 Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence that may present during 
participation in the study and which may or may not have a causal relationship with study procedures 
and/or products tested in this study. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the 
study procedures and/or products. 
Any increase in the severity and/or the frequency of a concomitant disease is considered an AE. 
11.1.2 Serious Adverse Event 
A Serious Adverse Event is any adverse event that: 
• results in death; 
• is life-threatening; 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity; 
• results in a congenital anomaly / birth defect; 
• requires immediate medical or surgical intervention. 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE, when, based on appropriate medical judgment, the event may jeopardize 
the participant, or the participant may require medical or surgical intervention to prevent one of the 
outcomes listed in the above definitions. 
The term "life-threatening" in the definition of "serious" refers to an event in which the participant was 
at risk of death at the time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be recorded as an 
SAE; however, they will be recorded as AE only. Any AE that occurs during this pre-planned 
hospitalization will be considered according to the above definitions. 
11.2 COLLECTION OF SAFETY EVENTS FROM PARTICIPANTS 
Information recorded when collecting AEs will include: thorough description of the AE, seriousness 
assessment, start and stop dates (if known), circumstances leading up to the event, clinical elements 
such as clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence, the action taken with the investigation 


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product/procedures due to the AE, the participant`s disposition in the study after the occurrence of the 
AE and the final outcome of the AE (if known). 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall be 
evaluated and recorded. 
AEs should be collected using questionnaires and face-to-face interviews with the participant. The 
Adverse Effects Form is a targeted checklist-based questionnaire with items selected to detect common 
side effects from product use. This questionnaire also contains an open-ended section for participants to 
record any additional effects.  
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs and/or 
symptoms, it should be preferentially provided as the AE or SAE term, rather than the individual signs 
and/or symptoms. Otherwise, each one of those signs and/or symptoms should be reported separately 
as event terms. 
11.2.1 Period of Collection 
All existing health conditions identified during the Screening Period will be recorded as concomitant 
disease and the participant’s eligibility will be reviewed. Any AEs which occur during the screening 
session will be captured by the study site staff and assessed by the Investigator or designee in order to 
establish relationship or relatedness in respect to study procedures. 
Any new, clinically relevant, abnormal finding detected during the study or worsening of a pre-existing 
condition/concomitant disease will be documented as an AE or an SAE. 
11.3 ASSESSMENT OF ADVERSE EVENTS 
11.3.1 Intensity of Adverse Events 
For each AE/SAE, the intensity will be graded on a 3-point intensity scale: 
• Mild:  The AE is easily tolerated and does not interfere with daily activity. 
• Moderate: The AE interferes with daily activity, but the participant is still able to function. 
• Severe: The AE is incapacitating and requires medical intervention. 
11.3.2 Relationship to Study Procedures 
In general, all AEs and SAEs will be assessed by the Investigator or designee as either ‘related’ or ‘not 
related’.  
• Not related: The temporal relationship of the clinical event to study procedures and/or the 
study medication makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient explanation for the 
observed event. 
• Related: The temporal relationship of the clinical event to study procedures and/or the study 
medication makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for the 
observed event. 


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11.4 FOLLOW-UP OF NON-SERIOUS AND SERIOUS ADVERSE EVENTS 
Non-serious AEs will not be followed-up by the Investigator or designee after the end of study. The 
Investigator or designee will refer the participant to their Primary Care Provider for follow up of those 
AE(s) until they have resolved, stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found. 
Serious AEs will be followed up by the Investigator or designee, despite their continuation after the end 
of study, until their resolution, stabilization (i.e., no worsening of the condition), or an acceptable 
explanation has been found (e.g. a chronic condition). 
11.5 REPORTING OF SAFETY EVENTS TO IRB 
The Principal Investigator will report all serious adverse events relating to the study in an expedited 
manner to the Institutional Review Board (IRB) office in accordance with the Center’s standard 
operating procedures and GCP reporting guidelines. 
11.6 REPORTING OF SAFETY EVENTS TO FDA 
The Principal Investigator will report any suspected adverse reaction to study treatment that is both 
serious and unexpected to the FDA following established Safety Reporting guidelines. 
11.7 REPORTING AND FOLLOW-UP OF PREGNANCIES 
All participants who are determined to be pregnant after enrollment will be discontinued from the 
study. Advice on the risk of smoking and smoking cessation will be provided by the study doctor (or 
qualified staff) and participants will be referred to the respective health care facility/health care 
provider for further support. 
The Investigator is responsible for informing the IRB of any pregnancy that occurs during the study, and 
its outcome, according to local regulations. 
11.8 ADVERSE EVENT LEADING TO DISCONTINUATION 
If a participant is discontinued from the study because of an AE, the Investigator or designee will follow 
up until the AE(s) has/have been resolved, stabilized (i.e., no worsening of condition), or until an 
acceptable explanation has been found. 
 DATA MANAGEMENT 
12.1 DATA COLLECTION PROCEDURES 
Trained study personnel will be responsible for capturing the data from the observations, tests, and 
assessments specified in the protocol and in the source documents. 
The Investigator has ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. Any corrections made to source documents 


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must be clearly recorded, without obscuring the original values and be accompanied by the date of 
change and identification of the person making the change.  
Study staff will maintain appropriate medical and research records for this study, in compliance with ICH 
E6, Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
participants.  Study staff will permit authorized representatives and regulatory agencies to examine (and 
when required by applicable law, to copy) research records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety, progress and data validity.   
12.2 PROTOCOL DEVIATIONS / NONCOMPLIANCE 
Protocol deviations are defined as deviations from the study procedures as defined in this document, 
whether intentional or unintentional that may affect the participant’s rights, safety, or well-being and/or 
the completeness, accuracy and reliability of the data. 
Noncompliance that meets the above definition must be reported to the IRB within 10 days of becoming 
aware of the noncompliance. 
12.3 DATA CAPTURE 
All data are collected from participants using paper documents or an electronic data capture system. All 
applicable data, as specified in the protocol, will be transferred to the database or applicable Case 
Report Forms. 
12.3.1 Salesforce.com 
Data will be collected for recruitment and screening purposes as stated within an Advarra IRB generic 
recruitment protocol. Unrelated to that protocol, pre-screening questionnaires will be attached to 
potential participant’s records on whether they qualify or are disqualified for this study. Questionnaires 
utilized for this study will be permanently attached to that potential volunteer’s record unless that 
information is requested to be removed by the participant. 
12.3.2 Survey Monkey 
Survey Monkey uses some of the most advanced technology for Internet security that is commercially 
available today. This Security Statement is aimed at being transparent about our security infrastructure 
and practices, to help reassure that data is appropriately protected. Visit Survey Monkey privacy policy 
for more information on data handling. 
All Survey Monkey information systems and infrastructure are hosted in world-class data centers. These 
data centers include all the necessary physical security controls you would expect in a data center these 
days (e.g., 24×7 monitoring, cameras, visitor logs, entry requirements). SurveyMonkey has dedicated 
cages to separate our equipment from other tenants. In addition, these data centers are SOC 2 
accredited.  
12.3.3 Short Message Service (SMS) Messaging 
SMS Messaging will be utilized for the delivery of a hyperlink to a mobile device to collect study data. 
This data will be collected utilizing an electronic survey. The service utilized for these messages is 
textit.in. 


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12.3.4 Medrio 
All smoking behavioral and self-report measures will be captured initially using Medrio. Medrio is an 
electronic data collection system that records and performs analysis and reporting of data. Participant 
data will be kept within Medrio’s secure servers and may only be transmitted through a secure (SSL) 
download to our local server. Medrio’s servers are protected by high-end firewall systems, with 
vulnerability scans performed regularly. All services have quick failover points with redundant hardware, 
and complete encrypted backups are performed regularly. Medrio uses Transport Layer Security (TLS) 
encryption (SSL or HTTPS) for all transmitted internet data. All information collected within Medrio is 
compliant with 21 CFR 11 requirements. 
12.4 MISSING DATA 
Missing data will remain as missing, i.e., no attempt will be made to impute missing values and only 
observed values will be used in data summarizations and analysis. 
12.5 DATA HANDLING 
Data of all participants enrolled including screening failures and AE/SAEs during the study (from the time 
of informed consent to the end of the study of the participant) will be captured in the source 
documents. 
12.6 DATA VALIDATION 
Data that are entered will be verified and edit checked to ensure accuracy. Inconsistencies that arise 
from these checks will be resolved and documented by study staff. 
12.7 DATABASE LOCK 
Upon completion of the trial, after data entry is complete, the data has been cleaned, and the principal 
investigator has reviewed and provided approval, the database will be locked, and final write access will 
be removed. 
 PLANNED STATISTICAL METHODS 
All data measures (e.g., withdrawal symptoms questionnaires, smoking history, smoking diaries, etc.) are 
captured initially using paper or an electronic data capture system. Verified data files will be analyzed 
using Statview or SAS (Statview, SAS Institute, Cary NC). Data will be inspected for outliers and if 
sufficiently extreme (Chauvenet’s criterion, after verifying normality of distributions) will be censored 
from the data analysis.  
13.1 EFFICACY AND TOLERABILITY 
13.1.1 Abstinence Outcomes 
Abstinence at each time point will be defined by a self-report of no cigarette smoking (not even a puff) 
since the prior session, confirmed by an expired air CO reading of less than 5 ppm. The primary 


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abstinence outcome will be abstinence during weeks 8-11 post-quit date. An intent-to-treat approach 
will be taken in which any participants lost to follow-up after the point of randomization, or who have 
relapsed prior to the end of treatment (week 11 post-quit) will be counted as non-abstinent (in 
accordance with recent guidelines from the FDA). A secondary smoking abstinence outcome will be 7-
day point abstinence at 6 months post-quit, for participants who have not relapsed prior to the end of 
treatment. The main goal of the 6-month follow-up is to assess the persistence of therapeutic effects for 
those who do achieve end-of-treatment abstinence. This information will be helpful in determining the 
treatment duration in future Phase 3 clinical trials. The main hypothesis to be evaluated in this pilot 
study is that the incidence of varenicline-associated side effects, specifically nausea, will be diminished 
by co-administration of hydroxyzine, relative to historical benchmarks (see below). A one-tailed test of 
abstinence will be conducted, however, comparing the proportion of participants abstinent during 
weeks 8-11 to the historical benchmark of 45% abstinence, to provide evidence that abstinence is not 
significantly lower than it would be with varenicline alone.  There is no reason to expect that abstinence 
rate would be reduced by hydroxyzine; if anything, abstinence would be expected to be enhanced by 
amelioration of varenicline-associated side effects and by potential effects of H1 antagonists to reduce 
nicotine reward.35 
13.1.2 Side Effects / Tolerability 
The hypothesis that hydroxyzine reduces the incidence of nausea, one of the most common side effects 
of varenicline, will be evaluated by comparison to the benchmark of 30% (20% above placebo rate of 
10%) observed in clinical trials of varenicline.36 Initially, 25 participants will be recruited and then the 
possibility of recruiting 25 more (total N=50) depending on an interim analysis, as follows: 
 
• If 0-3 participants out of 25 (12% or less) report nausea, we would conclude the treatment is highly 
promising at the interim stage and go directly to an RCT (Branch 1). 
• If 4-6 participants (out of 25) report the side effect, then the treatment will be deemed sufficiently 
promising to recruit an additional 25 participants (Branch 2). If 10 or less of the total 50 report 
the side effect of nausea (20% or less), a follow-up RCT would be warranted; otherwise the 
treatment would be deemed unpromising. 
• If 7 or more out of 25 (28% or more) report the side effect of nausea in the interim analysis, then we 
would conclude it is futile to continue the pilot and the study would be terminated (Branch 3). 
The frequency of treatment-emergent side effects (i.e., those that begin or worsen after the initiation of 
treatment) will be tabulated. Due to the problem of Type II error posed by significance testing numerous 
side effect outcomes (especially if corrections are imposed for multiple comparisons), descriptive 
statistical methods will instead be used, supplemented by calculation of confidence intervals and p-
values as a flagging device to highlight differences worthy of further attention.37 Hypothesis testing will 
be conducted for only two outcomes: 1) proportion of participants that withdraw from the study due to 
side effects; 2) overall adherence (i.e., proportion of scheduled doses taken) assessed by daily 
medication diaries and returned capsules.  
13.1.3 Statistical Power 
Monte Carlo simulations conducted by our statistical consultant (Dr. Dan Bauer) revealed that if the 
combination hydroxyzine/varenicline treatment is no better than varenicline alone (null of 30% 
incidence of nausea is true) the following would occur: 
-          3% go into Branch 1 (highly promising) 
-          31% go into Branch 2 (larger pilot) 


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-          66% go into Branch 3 (early evidence of futility) 
-          Overall Type I error rate of 9% 
If the new treatment yields a side effect rate of 15% (versus null of 30%) then: 
-          47% go into Branch 1 (highly promising) 
-          46% go into Branch 2 (larger pilot) 
-          7% go into Branch 3 (futile) 
-          Overall power of 86% 
If the new treatment yields a side effect rate no worse than placebo of 10% (versus null of 30%) then:  
-          77% go into Branch 1 (highly promising) 
-          22% go into Branch 2 (larger pilot) 
-          1% go into Branch 3 (futile) 
-          Overall power of 98% 
Thus, to detect a clinically important reduction in side effects (a relative reduction by at least 50%, from 
an incidence of 30% to 15% or less), the power exceeds 86%. The Type I error of the overall approach is 
9%. 
13.2 INTERIM ANALYSIS 
An interim analysis will be conducted after results are collected from the first 25 participants, in order to 
determine whether the trial will stop, or an additional 25 participants will be enrolled, as described above. 
  
 ETHICS AND REGULATIONS 
14.1 IRB APPROVAL 
The protocol, informed consent document and relevant supporting information must be submitted to 
the IRB for review and must be approved before the study is initiated. In addition, any participant 
recruitment materials must be approved by the IRB prior to being used.  
Any change to the protocol must be submitted to the IRB for review and approval before 
implementation. A protocol change intended to eliminate an apparent immediate hazard to participants 
may be implemented immediately provided the reviewing IRB are notified within 10 working days. 
14.2 INVESTIGATIONAL NEW DRUG APPLICATION 
An Investigational New Drug (IND) application is not required for either medication since both 
medications have been approved by the FDA for the intended purposes. Since varenicline and 
hydroxyzine are FDA-approved medications, marketed in the United States, they do not require an IND.  
This study is not intended to support a new indication, support a change in labeling, support a change in 
advertising, nor does it involve a change in dosage level or route of administration. 


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14.3 GCP AND REGULATORY REQUIREMENTS 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
requirements. The study must be conducted in accordance with the regulations of the United States 
Food and Drug Administration (FDA) as described in 21 CFR 50 and 56, applicable laws and the IRB 
requirements.  
14.4 PARTICIPANT INFORMATION AND CONSENT 
It is the responsibility of the investigator to provide each participant with full and adequate verbal and 
written information using the IRB-approved informed consent form (ICF), including the objective and 
procedures of the study and the possible risks involved before inclusion in the study. Informed consent 
must be obtained prior to performing any study-related procedures.  
The signed and personally dated original and completed ICF(s) must be kept by the Investigator and filed 
in the Investigator study file at the site or with the participant’s files and a copy must be given to the 
participant. The participant will be informed that if they discontinue from the study, the data collected 
until the point of discontinuation will be maintained as part of the study data and the samples 
collected prior to discontinuation will be analyzed, unless they refuse in writing. 
14.5 AMENDMENT TO INFORMED CONSENT FORM 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of the ICF is 
necessary, the Investigator or designee will ensure that the documents have been reviewed and 
approved by the IRB before participants are informed and sign the amended ICF (including date and 
time). 
 ADMINISTRATIVE CONSIDERATIONS 
15.1 PARTICIPANT CONFIDENTIALITY 
All information obtained during the conduct of the study with respect to the participants' state of health 
will be regarded as confidential. A statement to this effect will be written in the information provided to 
the participant. An agreement to disclose any such information will be obtained from the participant in 
writing and signed by the participant, in compliance with all local and national data protection and 
privacy legislation. 
Study records that identify participants will be kept confidential as required by law. Except when 
required by law, participants will not be identified by name, social security number, address, telephone 
number, or any other direct personal identifier in study records disclosed outside of Rose Research 
Center. For records disclosed outside of Rose Research Center, participants will be assigned a unique 
code number. The key to the code will be kept separate from the locked file where the study records are 
stored. 


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15.2 RECORD RETENTION 
All records of data, in any form, will be maintained by Rose Research Center as required by ICH/GCPs. 
Essential documents will be retained for at least 15 years after completion of the study. 
Appropriate measures will be taken to prevent accidental or premature destruction of these documents. 
 
 


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1.  
Jamal A. Current Cigarette Smoking Among Adults — United States, 2005–2015. MMWR Morb 
Mortal Wkly Rep. 2016;65. doi:10.15585/mmwr.mm6544a2 
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Carter BD, Freedman ND, Jacobs EJ. Smoking and mortality--beyond established causes. N Engl J 
Med. 2015;372(22):2170. doi:10.1056/NEJMc1503675 
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Xu X, Bishop EE, Kennedy SM, Simpson SA, Pechacek TF. Annual healthcare spending 
attributable to cigarette smoking: an update. Am J Prev Med. 2015;48(3):326-333. 
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Panel TU and DG. Table 6.26, Meta-analysis (2008): Effectiveness and abstinence rates for 
various medications and medication combinations compared to placebo at 6-months postquit (n = 83 
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Harmey D, Griffin PR, Kenny PJ. Development of Novel Pharmacotherapeutics for Tobacco 
Dependence: Progress and Future Directions. Nicotine Tob Res. 2012;14(11):1300-1318. 
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Doherty K, Kinnunen T, Militello FS, Garvey AJ. Urges to smoke during the first month of 
abstinence: relationship to relapse and predictors. Psychopharmacology (Berl). 1995;119(2):171-178. 
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McKee SA, Sinha R, Weinberger AH, et al. Stress decreases the ability to resist smoking and 
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Brown RA, Lejuez CW, Strong DR, et al. A prospective examination of distress tolerance and early 
smoking lapse in adult self-quitters. Nicotine Tob Res. 2009;11(5):493-502. doi:10.1093/ntr/ntp041 
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Ashare RL, Lerman C, Tyndale RF, et al. Sleep Disturbance During Smoking Cessation: 
Withdrawal or Side Effect of Treatment? J Smok Cessat. 2017;12(2):63-70. doi:10.1017/jsc.2016.11 
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Elrashidi MY, Ebbert JO. Emerging drugs for the treatment of tobacco dependence: 2014 update. 
Expert Opin Emerg Drugs. 2014;19(2):243-260. doi:10.1517/14728214.2014.899580 
11.  
Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial 
agonist for smoking cessation. J Med Chem. 2005;48(10):3474-3477. doi:10.1021/jm050069n 
12.  
Reus VI, Obach RS, Coe JW, et al. Varenicline: new treatment with efficacy in smoking cessation. 
Drugs Today Barc Spain 1998. 2007;43(2):65-75. doi:10.1358/dot.2007.43.2.1069956 
13.  
Ferreri M, Hantouche EG. Recent clinical trials of hydroxyzine in generalized anxiety disorder. 
Acta Psychiatr Scand Suppl. 1998;393:102-108. 
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Sadek B, Khanian SS, Ashoor A, et al. Effects of antihistamines on the function of human α7-
nicotinic acetylcholine receptors. Eur J Pharmacol. 2015;746:308-316. doi:10.1016/j.ejphar.2014.10.046 


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Levin ED, Slade S, Wells C, et al. Histamine H(1) antagonist treatment with pyrilamine reduces 
nicotine self-administration in rats. Eur J Pharmacol. 2011;650(1):256-260. 
doi:10.1016/j.ejphar.2010.10.013 
16.  
Meclizine as a Potential Smoking Cessation Treatment - Full Text View - ClinicalTrials.gov. 
https://clinicaltrials.gov/ct2/show/study/NCT01443858. Accessed August 16, 2017. 
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DrugBank, ed. Meclizine. In: DrugBank. ; 2017. https://www.drugbank.ca/drugs/DB00737. 
18.  
Simons FE, Simons KJ, Frith EM. The pharmacokinetics and antihistaminic of the H1 receptor 
antagonist hydroxyzine. J Allergy Clin Immunol. 1984;73(1 Pt 1):69-75. 
19.  
Hays JT, Ebbert JO, Sood A. Efficacy and safety of varenicline for smoking cessation. Am J Med. 
2008;121(4 Suppl 1):S32-42. doi:10.1016/j.amjmed.2008.01.017 
20.  
Llorca P-M, Spadone C, Sol O, et al. Efficacy and safety of hydroxyzine in the treatment of 
generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry. 2002;63(11):1020-1027. 
21.  
Hydroxyzine Side Effects in Detail. Drugs.com. https://www.drugs.com/sfx/hydroxyzine-side-
effects.html. Accessed August 30, 2017. 
22.  
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119-1127. 
23.  
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. Confirmatory factor 
analyses and reliability of the modified cigarette evaluation questionnaire. Addict Behav. 
2007;32(5):912-923. doi:10.1016/j.addbeh.2006.06.028 
24.  
Matthews A, Haas DM, O’Mathúna DP, Dowswell T. Interventions for nausea and vomiting in 
early pregnancy. Cochrane Database Syst Rev. 2015;(9):CD007575. 
doi:10.1002/14651858.CD007575.pub4 
25.  
Kurucu N, Durmaz M. Effect of Hydroxyzine in Controlling Acute Chemotherapy-Induced 
Vomiting in Children: A Randomised Trial. In: ; 2012. doi:10.4999/uhod.10066 
26.  
FastStats. https://www.cdc.gov/nchs/fastats/body-measurements.htm. Published March 19, 
2019. Accessed April 5, 2019. 
27.  
Halperin AC, McAfee TA, Jack LM, et al. IMPACT OF SYMPTOMS EXPERIENCED BY VARENICLINE 
USERS ON TOBACCO TREATMENT IN A REAL WORLD SETTING. J Subst Abuse Treat. 2009;36(4):428-434. 
doi:10.1016/j.jsat.2008.09.001 
28.  
Varenicline Side Effects in Detail. Drugs.com. https://www.drugs.com/sfx/varenicline-side-
effects.html. Accessed August 30, 2017. 
29.  
Research C for DE and. Drug Safety and Availability - FDA Drug Safety Communication: Safety 
review update of Chantix (varenicline) and risk of cardiovascular adverse events. 
https://www.fda.gov/Drugs/DrugSafety/ucm330367.htm. Accessed October 30, 2017. 
30.  
Leung DY, Lam T, Chan SS. Three versions of Perceived Stress Scale: validation in a sample of 
Chinese cardiac patients who smoke. BMC Public Health. 2010;10:513. doi:10.1186/1471-2458-10-513 


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JULIAN LJ. Measures of Anxiety. Arthritis Care Res. 2011;63(0 11). doi:10.1002/acr.20561 
32.  
Tluczek A, Henriques JB, Brown RL. Support for the Reliability and Validity of a Six-Item State 
Anxiety Scale Derived From the State-Trait Anxiety Inventory. J Nurs Meas. 2009;17(1):19-28. 
33.  
CHANTIX® (varenicline tartrate) | Pfizer Medical Information - US. 
https://www.pfizermedicalinformation.com/en-us/chantix. Accessed October 31, 2017. 
34.  
Swan GE, Javitz HS, Jack LM, et al. Varenicline for Smoking Cessation: Nausea Severity and 
Variation in Nicotinic Receptor Genes. Pharmacogenomics J. 2012;12(4):349-358. 
doi:10.1038/tpj.2011.19 
35.  
Levin ED, Slade S, Wells C, et al. Histamine H(1) antagonist treatment with pyrilamine reduces 
nicotine self-administration in rats. Eur J Pharmacol. 2011;650(1):256-260. 
doi:10.1016/j.ejphar.2010.10.013 
36.  
Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine 
receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a 
randomized controlled trial. JAMA. 2006;296(1):47-55. doi:10.1001/jama.296.1.47 
37.  
ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International 
Conference on Harmonisation E9 Expert Working Group. Stat Med. 1999;18(15):1905-1942. 
 
 


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Appendix 1 – Perceived Stress Scale 10-Item (PSS-10) 
 
 
 


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Appendix 2 – State-Trait Anxiety Inventory 6-Item (STAI) 
 
 


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Appendix 3 - Patient Health Questionnaire (PHQ-9) 
 
 
 
 


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Appendix 4 – Minnesota Nicotine Withdrawal Scale Revised (MNSW-R) 
 
 
 
 
 
 


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Appendix 5 – Fagerström Test for Nicotine Dependence (FTND) 
 
 
 
 


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Appendix 6 – The Wisconsin Predicting Patients' Relapse Questionnaire (WI-PREPARE) 
 


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Appendix 7 - Research Participant Payment Verification Form  
 
 
RESEARCH PARTICIPANT PAYMENT VERIFICATION FORM 
Receipt for Payment: 
In order for Rose Research Center to meet its obligations to the Internal Revenue Service we are required to obtain the 
following information. Payment received as compensation for participation in research is considered taxable income.  You are 
responsible for paying any state, federal or Social Security taxes on the money you receive.  If your total payment exceeds $600 
in any one calendar year, we are required to report this information to the Internal Revenue Service (IRS).   
The Payment Verification Form will be used in order to process your payments only. Once your information has been entered 
into the Greenphire payment system, this form will be destroyed. Until that time, the form will be kept in a secure and locked 
area at all times. Your information will not be connected to your responses to the interviews, surveys, questionnaires or with 
your participation in this study. 
Full Name: 
 
______________________________________________ 
Social Security Number: 
______________________________________________ 
Permanent Home Address:  
_________________________________________ 
_________________________________________ 
_________________________________________ 


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Appendix 8 – Smoking History 
 
 
 
SMOKING HISTORY 
What brand of cigarettes do you smoke? _____________________________ 
Color of cigarette pack? __________________________________________ 
Size:  
Flavor: 
Pack type:     
Filtered? 
1.  How many cigarettes do you smoke a day? _________________cigs per day 
 
2.  How old were you when you first smoked a cigarette? _________________ years old 
3.  How old were you when you became a regular smoker? ________________ years old 
4.  How many years have you been a regular smoker? ________________ years 
5.  How many times have you tried to seriously quit smoking (for at least 1 day)? __________ attempts 
6. Since you first started smoking, what was the longest period of time that you were able to stay off cigarettes? (If less than 1 day, 
do not include time sleeping) __________________________ 
 Hours 
 Days 
 Weeks 
 Months 
 Years 
7. Have you been a regular for the past 12 months? 
 Yes  
 No  
8.  Do you have the desire to quit smoking in the next 30 days? 
 Yes 
 No  
9.  Did your mother smoke cigarettes while pregnant with you? 
 Yes  
 No  
 I don't know  
10.  Does someone you live with smoke cigarettes? 
 Yes 
 No  
11.  Have you smoked cigar in the past 14 days? 
 Yes 
 No  
12. Have you smoked a pipe, hookah or an e-cigarette in the past 14 days? 
 Yes 
 No  
13.  Have you used snuff or chewing tobacco in the past 14 days? 
 Yes 
 No  
14. Do you wake in the middle of the night to smoke? 
 Yes 
 No  
 Kings  
 Regulars 
 72's  
 100's  
 120's  
 Menthol 
 Non-menthol 
 Hard pack  
 Soft pack  
 Filtered  
 Unfiltered  


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Appendix 9 – Registration Form 
 
 
 


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Appendix 10 – Medical History Form 
 


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Appendix 11- Review of Systems Form 
 
 
REVIEW OF SYSTEMS 
 
Are you currently (in the last 30 days) having/ being treated for any of the following conditions: 
 
General: (____ none of these apply) 
 Unexplained weight loss or gain 
 Fever or chills 
 Trouble Sleeping 
 Fatigue/ Lack of energy 
 Weakness 
 
 
Skin: (____ none of these apply) 
 Rashes 
 Itching 
 Color changes 
 Lumps 
 Dryness 
 Hair and nail changes 
 
Head: (____ none of these apply) 
 Headache 
 Head Injury 
 
 
Ears: (____ none of these apply) 
 Decreased hearing 
 Earache 
 Ringing in ears  
 
Eyes: (____ none of these apply) 
 Vision problems 
 Blurry or double vision 
 Redness 
 Specks 
 Flashing lights 
 Pain 
 
 
 
Nose: (____ none of these apply) 
 Stuffiness 
 Itching 
 Nose Bleeds 
 Discharge 
 Sinus pain 
 
 
Throat: (____ none of these apply) 
 Teeth/gum problems  
 Sore tongue  
 Thrush 
 Dentures 
 Dry mouth 
 Non-healing sores 
 Hoarseness 
 Sore throat 
 Difficulty swallowing 
 
 
 
Neck: (____ none of these apply) 
 Lumps 
 Pain 
 Swollen glands 
 Stiffness 
 
 
 
Respiratory: (____ none of these apply) 
 Cough (dry or wet, productive) 
 Coughing up blood 
 Wheezing 
 Shortness of breath 
 Painful breathing 
 
 
Cardiovascular: (____ none of these apply) 
 Chest pain or discomfort 
 Difficulty breathing lying down 
 Suddenly awaking from sleep with 
shortness of breath 
 Tightness 
 Swelling 
 Heart pounding/ Fluttering/ 
Palpitations  
 Shortness of breath with activity 
 
 
 
Gastrointestinal: (____ none of these apply) 
 Swallowing difficulties 
 Change in bowel habits 
 Yellow eyes or skin 
 Heartburn 
 Rectal bleeding 
 Change in appetite 
 Constipation 
 Diarrhea 
 Nausea 
 Vomiting 
 Stomach pain 
 
 
Urinary: (____ none of these apply) 
 Frequency 
 Blood in urine 
 Change in urinary strength 
 Urgency 
 Pain with urination 
 Incontinence 


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REVIEW OF SYSTEMS 
 
 
Vascular: (____ none of these apply) 
 Calf pain with walking 
 Leg cramping 
 Leg pains 
 
 
 
Musculoskeletal: (____ none of these apply) 
 Muscle or joint pain 
 Back pain 
 Swelling of joints 
 Stiffness 
 Redness of joints 
 Trauma 
 
Neurologic: (____  none of these apply) 
 Dizziness 
 Weakness 
 Tremor 
 Fainting 
 Numbness 
 Shaking episodes 
 Tingling 
 
 
 
Hematologic: (____ none of these apply) 
 Bruise easily 
 Bleed easily 
 
 
 
 
Endocrine: (____ none of these apply) 
 Heat or cold intolerance 
 Frequent urination 
 Change in appetite 
 Sweating  
 Thirst 
 
 
Psychiatric: (____  none of these apply) 
 Nervousness 
 Memory loss 
 Feeling down 
 
Females only: (____ none of these apply) 
 Pregnant or currently breast feeding 
 
 
Office use only: 


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Appendix 12 – Employment History 
 
 
 
 
 
EMPLOYMENT HISTORY 
1.  What is the highest degree you have completed? 
 High school diploma or G.E.D.  
 Technical degree  
 Two year associates degree (e.g. A.A.)  
 Four year undergraduate degree (e.g. B.A., B.S.)  
 Professional degree (e.g. P.A., R.N.)  
 Master’s degree (e.g. M.A., M.S., M.B.A.)  
 Doctorate (e.g. Ph. D., M.D., J.D.)  
 Other_______________________  
2.  How many years of formal education have you completed: (Include grade school and higher) ________ 
3.  What is your current employment status? 
 Not employed (please answer question 4) 
 Part-Time work  
 Full-time work  
4.  If not employed is selected, please specify your answer: 
 Education (Full-time student)  
 Retired  
 Medical leave  
 Homemaker  
 Laid off  
 Other _______________________________  
5.  What is your current job title; if no longer employed, in what position were you last employed?  
 
_____________________________________________________________________________________________ 
6.  How physically demanding is your current employment? 
 Not employed  
 Not demanding at all  
 Very little demanding  
 A little demanding  
 Somewhat demanding  
 Moderately demanding  
 Very demanding  
 Extremely demanding  


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EMPLOYMENT HISTORY 
7.  How mentally or emotionally stressful is your current employment? 
 Not employed  
 Not stressful at all  
 Very little stress  
 A little stressful  
 Somewhat stressful  
 Moderately stressful  
 Very stressful  
 Extremely stressful  
 
8.  What is your gross (before taxes) annual household income? 
 < $16,000  
 $16,001- $32,000  
 $32,001- $48,000  
 $48,001- $64,000  
 $64,001- $80,000 
 $80,001- $96,000  
 >$96,000  
 
9.  What are your estimated total assets? (Include house, automobiles, stocks, savings, furniture, etc.). 
 <$50,000 
 $50,001- $100,000  
 $100,001- $200,000  
 $200,001- $300,000  
 $300,001- $400,000  
 $400,001- $500,000  
 $500,001- $750,000  
 >$750,001  
10.  How many people live in your household? ________ 


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Appendix 13 – Adverse Effects Form 
 
 
 
 
 
 
 
 
 
 


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Appendix 14 – Daily SMS Survey 
 
 
 


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Appendix 15 -Quit Assist Resource 
 
 
 


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Appendix 16 –SMS Observation Survey (after enrollment – prior to V2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 17 – Participant Instructions for Hydroxyzine 
 
 
 


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Appendix 18 – Participant Instructions for Varenicline 
 
 


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Appendix 19 – 6-Month Follow Up Survey 
 
 
 
 
 


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Appendix 20 – Cigarette Evaluation Questionnaire modified (mCEQ)