Varenicline OTC Trial on Efficacy and Safety
Phase: PHASE4
Conditions: Tobacco Dependence, Withdrawal Symptoms, Smoking Cessation
Sponsor: Arizona State University

   
   
   
 
This is to certify that the information contained herein is true and correct as reflected in the records of WCG IRB. WE CERTIFY 
THAT WCG IRB IS IN FULL COMPLIANCE WITH GOOD CLINICAL PRACTICES AS DEFINED UNDER THE U.S. FOOD AND 
DRUG ADMINISTRATION (FDA) REGULATIONS, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) 
REGULATIONS, AND THE INTERNATIONAL CONFERENCE ON HARMONISATION (ICH) GUIDELINES. 
 
Board Action: 03/03/2021 
  
 
 
Investigator Name: Scott James Leischow, PhD 
 
Board Action Date: 03/03/2021 
Investigator Address: Arizona State University, 425 N 3rd 
Street 
Phoenix, AZ 85004, United States 
Approval Expires: 02/21/2022 
Continuing Review Frequency: Annually 
Sponsor:  National Institutes of Health (NIH) 
Institution Tracking Number:   
Sponsor Protocol Number: 1R01DA044125 
Amended Sponsor Protocol Number:    
Study Number: 1183046 
IRB Tracking Number: 20180219 
Work Order Number: 1-1404472-1 
 
Protocol Title: Varenicline OTC Trial on Efficacy and Safety 
  
THE FOLLOWING ITEMS ARE APPROVED: 
Phone Screen Form - In Person #17243352.2 - As Submitted  
Phone Screen Form - Remote #30052000.0 - As Submitted  
Revised Protocol (01-26-2021)  
Consent Form - ASU - In Person [IN8]  
Consent Form - ASU - Remote Cohort [IN0]  
Advertisement - Print (ASU) In Person- Are you a smoker who #17243355.3 - As Submitted  
Advertisement - Print (ASU) Remote - Are you a smoker who #30052004.0 - As Submitted  
Advertisement - Print (LACT) In Person- Are you a smoker who #17243356.3 - As Submitted  
Advertisement - Print (LACT) Remote - Are you a smoker who #30052016.0 - As Submitted  
Advertisement - Social Media (LACT) In Person- Are you a smoker who #26596570.1 - As Submitted  
Advertisement - Social Media (LACT) Remote - Are you a smoker who #30052012.0 - As Submitted  
Advertisement - Social Media In Person - Any one of the following #26596569.1 - As Submitted  
Advertisement - Social Media Remote - Any one of the following #30052005.0 - As Submitted  
Revised Research Locations (02-18-2021) x1  
Telephone Screening Script - LACT In Person #17243354.3 - As Submitted  
Telephone Screening Script- In Person #17243353.3 - As Submitted  
Telephone Screening Script Remote - LACT #30052008.0 - As Submitted  
Telephone Screening Script Remote #30052006.0 - As Submitted  
 
  
Please note the following information: 
NOTE: IRB currently has CHANTIX (varenicline) Tablets Prescribing Information (12-2016) on file. 
 
Please have all future subjects sign the Consent Form(s) specified in this approval. 
  
THE IRB HAS APPROVED THE FOLLOWING LOCATIONS TO BE USED IN THE RESEARCH: 
Arizona State University, School of Nutrition and Health Promotion, Healthy Lifestyles Research Center, 425 N. 5th Street, 
Phoenix, Arizona  85004  
Los Angeles Clinical Trials, 847 North Hollywood Way, Suite 103, Burbank, California  91505  
Arizona State University, 850 N 5th Street, Phoenix, Arizona  85004    
 
  
ALL IRB APPROVED INVESTIGATORS MUST COMPLY WITH THE FOLLOWING: 
As a requirement of IRB approval, the investigators conducting this research will: 
• 
Comply with all requirements and determinations of the IRB. 
Certificate of 
Action 

COA Template 12-2020 
Board Action: 03/03/2021   
Page 2 of 3
• 
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o 
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o 
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o 
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• 
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for medical care incurred by human subject research subjects who experience research related injury will be 
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Reports from any data monitoring committee, data and safety monitoring board, or data and safety monitoring 
committee in accordance with the time frame specified in the research protocol. 
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Any findings from a closed research when those findings materially affect the safety and medical care of past subjects. 
Findings will be reported for 2 years after the closure of the research. 
  
For Investigator’s Brochures, an approval action indicates that the IRB has the document on file for the research. 
 
If the IRB approved an e-consent process that involves uploading the approved consent form to an e-consent platform, please 
ensure that the consent form(s) approved for your site is the version of the consent form that gets uploaded to the platform.  
If the board approves a change of Principal Investigator - Once approved, the new Principal Investigator is authorized by WCG 
IRB to carry out the study as previously approved for the prior Principal Investigator (unless the Board provides alternate 
instructions to the new Principal Investigator).  This includes continued use of the previously approved study materials.  The IRB 
considers the approval of the new PI a continuation of the original approval, so the identifying information about the study 
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DISTRIBUTION OF COPIES: 
Contact, Company 
Scott James Leischow, PhD, Arizona State University  
Ginger Hook, Arizona State University  

COA Template 12-2020 
Board Action: 03/03/2021   
Page 3 of 3
Ramya Turaga, PhD, Arizona State University   

Protocol #1R01DA044125  ver January 26, 2021              Page 1 of 43 
 
 
Date:  
 
 
 
January 26, 2021  
 
  
Protocol Title:            
Varenicline OTC Trial on Efficacy and Safety 
 
Protocol ID #: 
 
 
1R01DA044125 
Granting Agency:   
 
National Institute of Health/National Institute on Drug Abuse 
Agency Address:  
 
6001 Executive Blvd # 5128, 
Rockville, MD  20852 
 
 
 
 
Medical Monitor Name:  
1Frank LoVecchio, DO, MPH, FACEP, 3David P. Sklar, MD 
                                                                                 2Loraine Stern, MD 
Medical Monitor Address: 
1Arizona State University 
 
 
 
 
 
 
850 N. 5th St. 
Phoenix, Arizona 85004  
2Los Angeles Clinical Trials 
847 North Hollywood Way, Suite 103 
Burbank, CA 91505  
 
 
 
 
3Arizona State University - College of Health Solutions 
550 N 3rd St 
Phoenix, AZ 85004 
 
 
Sponsor and 
Principal Investigator:  
 
Scott Leischow, Ph.D. 
Research Site Address:  
Arizona State University  
425 N 5th Street 
Phoenix, AZ  85004 
 
Arizona State University 
850 N 5th Street 
Phoenix, AZ 85004 
 
 
Sub Investigator:  
 
Mitch Nides, Ph.D. 
Research Site Address:  
Los Angeles Clinical Trials (LACT) 
 
 
 
 
 
847 North Hollywood Way, Suite 103 
Burbank, CA 91505 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 2 of 43 
 
 
Table of Contents  
 
 
 
 
 
 
       Page 
            Cover Page 
1 
Table of Contents 
2 
A. Background and Significance 
 
 
 
 
 
 
3 
Overview-Tobacco Cessation Treatment  
 
 
 
 
3 
Varenicline History  
 
 
 
 
 
 
 
3 
B. Specific Aims 
 
 
 
 
 
 
 
 
5 
Primary Objectives 
 
 
 
 
 
 
 
5 
Secondary Objectives 
 
 
 
 
 
 
  
6 
Hypothesis 
 
 
 
 
 
 
 
 
6 
C. Experimental Methods 
 
 
 
 
 
 
 
6 
Study Design 
 
 
 
 
 
 
 
 
6 
Study Sites 
 
 
 
 
 
 
 
 
6 
Recruitment 
 
 
 
 
 
 
 
 
7 
Participants 
 
 
 
 
 
 
 
 
7 
Procedures by Study Visit 
 
 
 
 
 
 
7 
Inclusion Criteria  
 
 
 
 
 
 
 
10 
Exclusion Criteria  
 
 
 
 
 
 
 
11 
Behavioral Support 
 
 
 
 
 
 
 
11 
Risk Benefit Assessment  
 
 
 
 
 
 
11 
Investigational Product 
 
 
 
 
 
 
 
12 
Adverse Events 
 
 
 
 
 
 
 
 
13 
Participant Payment 
 
 
 
 
 
 
 
14 
EMA Sub-Study  
 
 
 
 
 
 
 
14 
Definition of Success 
 
 
 
 
 
 
 
16 
D. Data Safety Monitoring Plan 
 
 
 
 
 
 
16 
Participant Safety  
 
 
 
 
 
 
 
16 
E. Data Management and Analysis  
 
 
 
 
 
16 
Data Collection, Management and Storage 
 
 
 
 
16 
Sample Size 
 
 
 
 
 
 
 
 
16 
Data Sharing Plan 
 
 
 
 
 
 
 
17 
Statistical Analysis Plan  
 
 
 
 
 
 
17 
EMA Statistical Analysis  
 
 
 
 
 
 
18 
F. References  
 
 
 
 
 
 
 
 
19 
G. Appendix List 
 
 
1.Subject Demographics 
 
 
 
 
 
 
21 
 
2.Smoking Cessation Medical History 
 
 
 
 
22 
  
3. REALM 
 
 
 
 
 
 
 
 
23 
 
4. Minnesota Nicotine Withdrawal Survey 
 
 
 
 
24 
 
5. BP Acknowledgement Letter- ASU 
 
 
 
 
25 
 
6. BP Acknowledgement Letter – LACT 
 
 
 
 
27 
 
 
7. Fagerström Test of Cigarette Dependence 
 
 
 
29 
 
8. MD Authorization Letter 
 
 
 
 
 
 
30 
 
9. Smoking Status and Resource Utilization  
 
 
 
31 
 
10. Medication Compliance and Efficacy 
 
 
 
 
32 
 
11. Modified Cigarette Evaluation Questionnaire 
 
 
 
34 
 
12. Varenicline Use and Safety 
 
 
 
 
 
35 
 
13. EMA Prompts and Diary  
 
 
 
 
 
37 
 
14. Chantix Medication Guide 
 
 
 
 
 
39 
 
15. Suicidal Behavior Questionnaire  
 
 
 
 
43 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 3 of 43 
 
 
A.  BACKGROUND & SIGNIFICANCE 
Overview - Tobacco Cessation Treatments 
Tobacco use kills 480,000 individuals in the United States each year.1 Morbidity and 
mortality from tobacco use dwarfs all other preventable causes of mortality (alcohol, 
accidents, homicide, etc.) combined2 Most tobacco users want to quit, yet unlike other 
individuals who are dependent on illicit drugs or alcohol, they rarely seek formal treatment 
from physicians or cessation programs.3  Instead, most tobacco users attempt to go “cold 
turkey” and most fail numerous times before quitting.4,5 In fact, on any quit attempt, only 
about 6% of smokers achieve long-term success.6  
At present, there are five forms of NRT available in the U.S. (gum, patch, lozenge, 
nasal spray and inhaler), and two forms of non-nicotine medication (bupropion and 
varenicline [brand name Chantix™]). Quit rates can be doubled using cessation 
medications,7,8 yet despite the known efficacy of NRT and direct to consumer marketing by 
pharmaceutical companies, fewer than one in five smokers use some form of NRT during a 
quit attempt, either prescribed by a health care provider or over-the-counter (OTC).9 
Although some studies indicate that OTC medications significantly increase success at 
quitting when compared to using no medication,10 multiple studies have questioned whether 
OTC NRT is effective for smoking cessation.11-13   
Multiple studies, including meta-analyses and the recent large trial directly 
comparing varenicline, bupropion and nicotine patch, show that varenicline is the single 
most effective medication for smoking cessation.14-24 However, because it requires a 
prescription and fear of the box warning required by the FDA (see below), use of varenicline 
has been lower than NRT even though it is significantly more effective. Now that the box 
warning has been removed (Chantix™ label update, December 2016), it is essential to 
move more smokers who want to quit onto varenicline so that we can decrease smoking 
prevalence at an increased rapid pace. 
 
 
Varenicline History 
Varenicline acts as a partial agonist and does not produce the same intensity of 
response as a full agonist, even at high doses. Thus, the drug is classified as a selective 
nicotine receptor partial agonist (SNRPA) that works both to stimulate the nicotine receptor 
and block smoking reward at the α4β2 nicotinic receptor subtype.22 Of the many nicotine 
receptor subtypes, the α4β2 receptor is thought to mediate the rewarding properties of 
nicotine by modulating the release of dopamine in the nucleus accumbens (NA), or so-called 
“pleasure center” of the brain. In addition to its agonist effect, varenicline also has a powerful 
competitive antagonist effect on nicotine, due primarily to a substantially higher affinity for the 
α4ß2 receptor.22  
 
 
Efficacy of Varenicline. Studies have demonstrated the efficacy of varenicline, both 
in comparison with placebo14-24 and in comparison with the other FDA-approved smoking 
cessation medications.17 The USPHS and Cochrane meta-analyses found that varenicline 
results in the highest quit rates of any cessation medication mono therapy. Additionally the 
recent EAGLES study17 that compared varenicline, bupropion and nicotine patch in over 8000 
smokers with and without a history of psychiatric conditions showed clearly that in a head-to-
head study, varenicline is the single most effective medication. 
 
 
The dose of varenicline approved by the FDA for smoking cessation is 1mg b.i.d.  
What many scientists and clinicians seem to have missed is that a Phase II study completed 
by Oncken et al18 prior to the FDA approval showed that .5mg b.i.d. - half the dose of 
varenicline now recommended – appears to be as effective as the FDA-approved 1mg b.i.d. 
dose and results in fewer side effects. In the Oncken et al6 study, participants received 
behavioral intervention at each visit, so it was not an OTC study, but given these results, it is 

Protocol #1R01DA044125  ver January 26, 2021              Page 4 of 43 
 
 
important to assess the optimal dose to achieve efficacy while at the same time minimize side 
effects.   
 
 
Safety of Varenicline. Early studies on varenicline suggested that it was safe to use, 
with nausea, insomnia, abnormal dreams, headaches and flatulence and vomiting the most 
commonly reported side effects in the phase 2 and 3 studies.24 However, anecdotal post-
marketing reports of psychiatric adverse events including suicidal ideation and suicidal 
behavior led the FDA to require a box warning for varenicline in 2008.25-28 At the same time, 
the FDA required a similar box warning for bupropion, another prescription smoking cessation 
medication. The label change led to significantly less use of varenicline. Multiple studies 
(observational and RCTs) completed over the past eight years have provided strong evidence 
that the prevalence of these adverse events (AEs) was no greater than for placebo or NRT.28-
30 Pfizer requested that the FDA drop the box warning based on these results. However, the 
FDA had earlier required the implementation of the largest smoking cessation clinical trial 
ever conducted – which compared the safety and efficacy of varenicline, bupropion and 
nicotine patch to placebo – and indicated that they would not consider removing the box 
warning until the results of that study were available. The results of that study, called 
EAGLES, were recently published.17 They clearly show that 1 mg b.i.d. varenicline is as safe 
as nicotine patch and bupropion for smoking cessation, and that it is more effective than both.  
In addition, in a currently unpublished study, we have analyzed the outcomes of over 116,000 
smokers prescribed varenicline via the large Optum Labs clinical dataset, and those analyses 
reinforce the Eagles study:  IDC9 coding showed that fewer than 1% of those with and without 
a pre-existing psychiatric diagnoses experienced suicidal ideation or suicide attempts after 
they were prescribed varenicline.  Given these new results, both the FDA and the European 
Union have removed the box warning from varenicline, but the Warning and Precaution for 
potential psychiatric side effects still remains.  
 
 
Other rare safety concerns in the package insert include seizures, new or worsening 
heart or blood pressure problems, sleepwalking, increased sensitivity to alcohol, and serious 
allergic or skin reactions.    
Our Research on Rx to OTC switch. Our team has conducted multiple clinical trials 
to assess the safety and efficacy of smoking cessation medications as potential OTC 
products. With funding from NIDA, Leischow et al randomized smokers to receive nicotine 
patch in either an OTC condition or a health care provider (HCP) intervention.12 Finally, in the 
only study published to date on the efficacy of switching the nicotine inhaler from Rx to OTC,11 
we randomized smokers (n=500) to either an OTC or Rx condition and found that the Rx 
group had significantly higher quit rates at each time point than the OTC group except at 
week 52, and the OTC group quit rates were only 6% at one year (similar to using no 
medication). 
 
 
Dr. Nides enrolled 550 subjects in a 3-site nicotine patch OTC switch study in 1994. 
The study compared 6 weeks of 21mg patches versus placebo in a quasi-OTC storefront or 
office-building environment. At the end of treatment,16.8% in the active group vs. 9.6% in the 
placebo group had quit smoking. In a comparison arm in which participants paid to receive 
active patches, the quit rate was 19%. 
Lastly, both Dr. Nides and Leischow recently recruited over 170 participants at each of 
their sites on a large multi-center clinical trial assessing the safety and efficacy of a nicotine 
mouth spray, the result of which are not yet available. 
What each of these studies have in common is exploring whether a smoking cessation 
can be effective and safe when provided without behavioral support.  The focus of the current 
study is to likewise assess whether varenicline can be safe and effective when no behavioral 
support is provided. 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 5 of 43 
 
 
 
B.  SPECIFIC AIMS 
Three of the NRT products (i.e. patch, gum, and lozenge) are available as over-the-
counter (OTC) products because clinical trials have shown that they are safe and effective 
without healthcare provider involvement. The other two NRT products are not OTC for 
different reasons. The nasal spray has not been formally tested, perhaps because it is 
aversive when first used and has some potential for abuse liability. The nicotine inhaler is not 
effective as an OTC medication.1 
The two non-nicotine prescription medications, varenicline and bupropion, have not 
been considered for OTC status, in part because both had a ‘box warning’ placed on them by 
the FDA due to concerns that their use might cause or exacerbate psychiatric symptoms such 
as suicidal ideation or behavior. After multiple studies, including one of the largest smoking 
cessation trials (‘EAGLES’ study) ever conducted,17 it is clear that these medications do not 
cause statistically higher psychiatric adverse events than placebo or NRT. More specifically, 
in the EAGLES study, the FDA-approved dose of varenicline was found significantly more 
effective than bupropion, patch and placebo, and did not result in adverse events that 
necessitates a box warning, so the FDA removed the box warning. Thus, in combination with 
behavioral support, varenicline has the greatest probability of helping the most smokers quit 
with a similar adverse event profile to current OTC NRT products. 
Given these data, the time has come to explore whether varenicline is safe and 
effective when no behavioral support is provided as a foundation to assessing whether it can 
be safe and effective as an over-the-counter medication. This is important because in real 
world use, smokers often do not receive behavioral support, so there is value in assessing 
whether varenicline quit rates will still be high without that behavioral support. Moreover, since 
the adverse events from varenicline have been shown to be comparable to the OTC nicotine 
patch, this research will assess whether varenicline, in two different doses, can be safe and 
effective without a healthcare provider prescription.  More specifically, because earlier 
research found that .5mg twice a day (b.i.d.) varenicline is as effective as the currently FDA-
approved 1.0mg b.i.d. dosing but with lower incidence of nausea and sleep disturbance6, 
there is value in assessing whether the lower dose will work as well as the higher dose in an 
OTC environment. Lastly, to understand the within-person mechanisms explaining how and 
when OTC varenicline might improve cessation outcomes, as well as how side effects affect 
medication adherence, we will also assess experience with OTC varenicline via ecological 
momentary assessment (EMA). 
 
Primary Objectives 
1. To assess the safety and efficacy of the current FDA-approved 1 mg b.i.d. varenicline for 
smoking cessation in comparison with placebo when used in a simulated OTC study with no 
behavioral support provided. 
2. To assess the safety and efficacy of .5mg b.i.d. varenicline in comparison with 1mg b.i.d. 
varenicline and placebo when used in a simulated OTC study with no behavioral support 
provided. 
 
Secondary Objectives 
1. To evaluate whether subject specific characteristics (e.g. socioeconomic status, ethnicity, 
smoking history, etc.) moderate primary (safety and efficacy) and secondary (adherence) 
outcomes.  
2. To evaluate medication use patterns to assess whether varenicline is being used as 
indicated on the label, and to determine if medication adherence mediates cessation 
outcomes between-subjects. 

Protocol #1R01DA044125  ver January 26, 2021              Page 6 of 43 
 
 
3. In a subsample of participants, to examine how medication adherence, withdrawal, and 
side effects (e.g. nausea and sleep disturbance) vary within-subjects and are associated with 
smoking status using EMA in the first two critical weeks of medication use.  
 
Hypotheses 
1. Quit rates in the 1 mg b.i.d. varenicline condition will be significantly higher than the 
placebo medication condition when provided as an OTC medication. 
2. Quit rates in the .5 mg b.i.d. varenicline condition will be comparable to the 1mg b.i.d. 
varenicline condition, and will be significantly higher than the placebo medication condition, 
when provided as an OTC medication. 
3. Side effects will show a dose response relationship, with effects lowest in the placebo 
group. 
 
C. EXPERIMENTAL METHODS 
Study Design  
The primary objective of this study is to assess the efficacy of two different doses of 
varenicline used in a simulated OTC intervention relative to placebo (total N = 432). The 
design is a three-group placebo-controlled, double blind, block randomized clinical trial (as 
indicated in the figure), where participants will be randomly assigned to one of three 
conditions: (1) 1 mg 
b.i.d. varenicline for 
12 weeks, which is 
the current FDA-
approved dose, (2) 
0.5 mg b.i.d. 
varenicline for 12 
weeks, or (3) 
placebo.  
 
In addition, we will collect EMA data from 25 participants in each condition to obtain 
more granular data on the momentary relationship between varenicline use, adverse events, 
smoking, craving, and mood in the critical first two weeks after medication use begins. 
Outcomes of greatest interest are the within-person relationships between medication use 
(e.g., adherence), medication safety (e.g., adverse events), quit rates (self-report and 
biochemically validated), and factors that are associated with specific treatment outcomes. 
 
Study sites  
This study will be implemented at both Los Angeles Clinical Trials (LACT) and the Arizona 
State University. Dr. Nides will implement the study in Los Angeles; Dr. Leischow will 
implement the study in Phoenix.  
Human Subjects Protection.  Western IRB (WIRB) will be the IRB of record for this 
study, and the ASU IRB will receive the WIRB approvals and maintain documentation 
because it is the institution that has received funding from NIH.  WIRB approval is required for 
study implementation.  WIRB will maintain records for the study, and the ASU IRB will 
maintain a copy.  
 
Recruitment. We are making changes below due to the COVID-19 pandemic. The COVID-19 
pandemic has resulted in a drop in the number of potential participants contacting both sites 
in response to recruitment advertisements. Due to the lower number of respondents, we 
would like to increase the geographical area from which we are recruiting. By allowing for 
Screening 
Randomization
Varenicline 1mg b.i.d. (n=144) 
Varenicline 0.5mg b.i.d. (n=144) 
Placebo 0mg b.i.d. (n=144) 

Protocol #1R01DA044125  ver January 26, 2021              Page 7 of 43 
 
 
remote participation, we will we recruit nationally in addition to local site recruitment for in-
person participation. 
 
There will be two cohorts for this study going forward: one in-person cohort, and one remote 
cohort. We will recruit both cohorts via paid and free (e.g. Craigslist, Facebook, etc.) 
advertisements, as we have for other studies. We anticipate, based on previous studies, that 
we will need to recruit well over 2500 potential participants, of which 700 will be screened 
before 432 will ultimately be randomized. Fortunately, both sites can draw from large local 
populations that are demographically diverse. 
 
Participants. We will recruit male and female smokers of any race/ethnicity who are at least 
21 years of age (with no upper age limit). Our anticipated recruitment plan is:  60% male, 80% 
white, 10% black, 7% American Indian/Alaska Native, and 3% Hispanic. No vulnerable 
populations (eg incarcerated, mentally handicapped, etc) will be included; the specific 
inclusion/exclusion are below. 
 
Procedures by Study Visit for the In-person Cohort 
The Study Flow Chart and Schedule of Activities (Table 1) summarizes the data collection 
that will occur at each visit. The procedures that will occur at each visit are the following: 
 
Table 1. Study Flow Chart and Schedule of Activities for in-person visits 
Protocol Activity  
Screening/ 
Baseline 
Follow- up Visits (Week #s) 
End of 
Study Visit 
2 
4 
8 
12 
13 
26 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Assignment of ID number 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Body weight and height 
X 
 
 
 
X 
 
X 
Vital signs, e.g. blood pressure 
X 
 
 
 
 
 
 
REALM test of health literacy 
X 
 
 
 
 
 
 
Smoking and cessation 
medication history 
X 
 
 
 
 
 
 
FTCD 
X 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
Breath CO 
X 
 
X 
X 
X 
 
X 
Smoking status/Resource Utiliz. 
 
X 
X 
X 
X 
X 
X 
Minnesota Craving and 
Withdrawal symptoms (MNWS) 
X 
X 
X 
X 
X 
X 
X 
mCEQ 
 
X 
X 
X 
X 
 
 
Provide Product Information  
X 
 
 
 
 
 
 
Investigational product dispensed 
X 
 
X 
X 
 
 
 
Investigational product retrieved 
 
 
X 
X 
X 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 8 of 43 
 
 
Adherence and Efficacy 
Assessment 
 
X 
X 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Previous and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Suicidal Behavior Questionnaire 
X 
 
 
 
 
 
 
 
Initial telephone contact for the In-person Cohort: Potential participants will be asked to 
call a local or toll-free phone number to enroll. During this phone call, potential participants 
will be screened to assess eligibility based on the inclusion/exclusion criterion. Those still 
interested and qualified will be scheduled for the screening/baseline study visit and given 
directions to the study site. In addition to the eligibility screen, potential participants will also 
be screened for symptoms of COVID-19 (see COVID-19 Safety Procedures document) and 
have new safety procedures explained to them. 
 
Screening/Baseline for the In-person Cohort 
When potential participants arrive at the research site, the study will be described in written 
format and orally by study staff, and participants will be asked to sign the consent form. 
Participants will be asked to follow the guidelines outlined in the COVID-19 Safety 
Procedures document. The following will occur during Screening/Baseline: 
 
• Informed Consent 
• Subject Demographics (see Appendix 1) 
• Smoking, tobacco, and cessation medication use history (see Appendix 2) 
• Rapid Estimate of Adult Literacy in Medicine (REALM, see Appendix 3)  
• Minnesota Nicotine Withdrawal Scale (MNWS, see Appendix 4). This brief staff or 
subject administered form will assess cigarette-related craving and withdrawal. 
• Medical History—Pertinent medical history will be assessed and documented on the 
Medical History CRF by the study coordinator through a review of systems, allergies, 
and recent surgeries  
• Previous and Concomitant Medications. Medications taken within the previous 30 
days of the Screening/Baseline visit will be documented in the Concomitant 
Medication CRF  
• Body weight and height-height in meters (to the nearest cm) and weight in kilograms 
(to the nearest 0.1 kg in light indoor clothing and without shoes will be measured. 
• Vital signs including blood pressure and heart rate, measured after the subject has 
been seated and resting for at least 5 minutes.   
• Fagerström Test of Cigarette Dependence (FTCD, see Appendix 7). This 5 item 
subject completed questionnaire measures dependence on cigarettes. 
• Urine pregnancy test for all females 
• Urine drug screen. The urine test for drugs of abuse (eg opiates, amphetamines, 
benzodiazepines, cocaine or other substances) will be performed only at the 
Screening/Baseline Visit. Subjects who test positive will be excluded, unless they 
can provide the clinic with a copy of a current prescription for opioids or stimulants. 
• A portion of this urine will be stored for exploratory analysis of nicotine and nicotine 
metabolism that might be related to treatment outcomes, only at the ASU site. 
• Breath Carbon Monoxide test. The breath CO will be collected after a 15 second 
breath hold using the Bedfont Micro Plus (Bedfont Inc).   

Protocol #1R01DA044125  ver January 26, 2021              Page 9 of 43 
 
 
• If the subject requires study approval from their own physician, the Investigational 
Product will be dispensed upon their return to the clinic with the signed authorization 
(Appendix 8) 
• If subject meets all inclusion and exclusion criterion, a study ID will be assigned and 
he/she will be randomized in a 1:1:1 fashion to 1.0 mg b.i.d. varenicline, .5mg b.i.d. 
varenicline, or placebo. Participants and study staff will be blinded to the 
assignment.   
• Investigational Product educational information will be provided to participants 
• The first five weeks of Investigational Product dispensed 
• If randomized into the substudy, subjects will be instructed on how to respond to the 
text messages 
• Suicidal Behavior Questionnaire (Appendix 15) 
 
Week 2 Visit for the In-person Cohort 
• 
Telephone call 
• 
Minnesota Nicotine Withdrawal Scale  
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status and Resource Utilization Assessment (See Appendix 9) (Brief site 
administered questionnaires assessing smoking status, smoking cessation 
resources used since last study visit 
• 
Medication Adherence, and Perceived Efficacy Assessment (see Appendix 10) (Brief 
site administered questionnaires assessing pills taken since last study visit, and 
perceived efficacy of the medication.  
• 
Modified Cigarette Evaluation Questionnaire (mCEQ), see Appendix 11).  This 15-
item staff or subject administered questionnaire assesses the degree to which 
smokers experience the reinforcing effects of smoking.   
 
Weeks 4, 8 for the In-person Cohort 
• 
Breath Carbon Monoxide test  
• 
Minnesota Nicotine Withdrawal Scale 
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Medication adherence and Perceived Efficacy Assessment 
• 
Assess medication use by retrieving unused medication 
• 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
• 
Dispense additional Investigational Product 
*All questionnaires at this visit will take place, as much as possible, on the phone prior to 
the subject attending the visit as to minimize contact in response to the COVID-19 
pandemic 
 
Week 12 for the In-person Cohort 
• 
Body weight 
• 
Breath Carbon Monoxide test  
• 
Minnesota Nicotine Withdrawal Scale 
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status, and Resource Utilization Assessment  

Protocol #1R01DA044125  ver January 26, 2021              Page 10 of 43 
 
 
• 
Medication Adherence and Perceived Efficacy Assessment  
• 
Assess medication use by retrieving unused medication 
• 
Modified Cigarette Evaluation Questionnaire (mCEQ)  
*All questionnaires at this visit will take place, as much as possible on the phone prior 
to the subject attending the visit as to minimize contact in response to the COVID-19 
pandemic 
 
 
Week 13 (telephone call) for the In-person Cohort 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Adverse Events 
• 
Minnesota Nicotine Withdrawal Scale 
• 
Concomitant Medications including Chantix™ or other smoking cessation aids 
 
Week 26 for the In-person Cohort 
• 
Telephone call 
• 
Smoking Status and Resource Utilization Assessment  
• 
Body weight  
• 
Breath Carbon Monoxide test  
 
 
Visit Window. Table 2 shows the target and allowed windows for study visits.  Except for 
Week 2 where the telephone visit should be no more than 2 days on either side of the target 
visit day, the allowed window for each visit is 5 days before or after the target visit.  Visits 
outside of those ranges are allowed, but must be documented (eg vacation, difficulty 
contacting, illness, etc).   
 
 
Table 2. Target and allowed windows for study visits for the In-person 
and remote cohorts. 
Visit Week 
 
Target Day in Relation to 
Randomization Date 
Allowed 
Window (days) 
 
BL 
 
 
2 (call) 
14 
12-16 
4 
28 
23-33 
8 
52 
47-57 
12 
98 
93-103 
13 (call) 
105 
100-110 
26 
182 
177-187 
 
Inclusion Criteria for the In-person Cohort 
1. 21 years of age or older 
2. Self-reported daily smoker 
3. Breath CO > 10ppm 
4. Motivated to quit smoking completely within five weeks of the Screening Visit (>5 on 
reported motivation) 
5. Capable of and agree to complete study requirements 
6. Literate in English, self-report 

Protocol #1R01DA044125  ver January 26, 2021              Page 11 of 43 
 
 
7. Must be available for the duration of study 
8. Informed consent obtained 
9. Willing and able to provide additional data between visits using ecological momentary 
assessment (EMA) 
10. Must own study compatible smart-phone (iPhone or Android) 
 
Exclusion Criteria for the In-person Cohort 
1. Any self-report, diagnosis or treatment of heart attack, unstable angina, 
angioedema, seizures, cerebrovascular accident (CVA) within the last six months. 
2. Any self-report, diagnosis or treatment of bipolar, schizophrenia or suicidal ideation 
within the last six months. (For suicidal ideation a score of ≥7 on the Suicidal Behavior 
Questionnaire, see Appendix 15)   
3. Self-report of diagnosis or treatment for depression within the past six months, 
unless participant has written permission by their healthcare provider to participate  
4. Systolic blood pressure 160 or higher and/or diastolic blood pressure 100 or higher 
(see site applicable SOP for Evaluating and Reporting Blood Pressure and Appendices 
5 and 6 for participant handouts) 
 5. History of renal disease 
 
 6.  Allergy to any of the ingredients in varenicline 
 7.  Participation in another smoking cessation program or any type of clinical trial in the 
past 3 months 
 8.  Use of any smoking cessation medication in the past three months 
 9.  Any other medical condition(s) which the licensed study physician deems 
unacceptable for participation in this study 
10. Positive drug screen indicating possible substance abuse (eg opiates, 
amphetamines, benzodiazepines, cocaine or other substances), unless participant can 
show that the medication has been prescribed by licensed clinical provider. 
11. Consume greater than 21 alcohol drinks per week. 
12. No two members of the same household may participate in this study 
13. No study staff or their immediate family may participate in the study 
14. Females who are pregnant, breast feeding, or not currently using a medically 
approved form of birth control and unwilling to do so. 
Acceptable methods of birth control include abstinence, oral contraceptives, the 
contraceptive patch, the contraceptive ring, and condoms.  
 
Procedures by Study Visit for the Remote Cohort 
 
The Study Flow Chart and Schedule of Activities (Table 3) summarizes the data collection 
that will occur at each visit. The procedures that will occur at each visit are the following: 
 
Table 3. Study Flow Chart and Schedule of Activities for the Remote Cohort 
Protocol Activity  
Screening/ 
Baseline 1 
Screening/ 
Baseline 2 
Follow- up Visits (Week #s) 
End of 
Study 
Visit 
2 
4 
8 
12 
13 
26 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 12 of 43 
 
 
* Only if they report not smoking 
 
Initial telephone contact for the Remote Cohort: Potential participants will call a local or 
toll-free phone number to enroll. During this phone call, potential participants will be 
screened to assess eligibility based on the inclusion/exclusion criterion. Those still 
interested and qualified will be scheduled for the screening/baseline study visit.  
 
Screening/Baseline for the Remote Cohort – Visit 1 
A time will be scheduled for a phone call or Zoom meeting, the study will be described in 
written format and orally by study staff, and participants will be asked to electronically sign 
the consent form. The following will occur during Screening/Baseline: 
 
• Informed Consent (electronic) 
• Subject Demographics (see Appendix 1) 
• Smoking, tobacco, and cessation medication use history (see Appendix 2) 
• Rapid Estimate of Adult Literacy in Medicine (REALM, see Appendix 3)  
• Minnesota Nicotine Withdrawal Scale (MNWS, see Appendix 4). This brief staff or 
subject administered form will assess cigarette-related craving and withdrawal. 
• Medical History—Pertinent medical history will be assessed and documented on the 
Medical History CRF by the study coordinator through a review of systems, allergies, 
and recent surgeries  
• Previous and Concomitant Medications. Medications taken within the previous 30 
days of the Screening/Baseline visit will be documented in the Concomitant 
Medication CRF  
• Fagerström Test of Cigarette Dependence (FTCD, see Appendix 7). This 5 item 
subject completed questionnaire measures dependence on cigarettes. 
Randomization 
 
X 
 
 
 
 
 
 
Assignment of ID number 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
REALM test of health literacy 
X 
 
 
 
 
 
 
 
Smoking and cessation 
medication history 
X 
 
 
 
 
 
 
 
FTCD 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
Urine Cotinine  
 
X 
 
 
X* 
X* 
 
X* 
Smoking status/Resource Utiliz. 
 
 
X 
X 
X 
X 
X 
X 
Minnesota Craving and 
Withdrawal symptoms (MNWS) 
X 
 
X 
X 
X 
X 
X 
X 
mCEQ 
 
 
X 
X 
X 
X 
 
 
Provide Product Information  
 
X 
 
 
 
 
 
 
Investigational product dispensed 
 
X 
 
 
 
 
 
 
Investigational product retrieved 
 
 
 
 
 
X 
 
 
Adherence and Efficacy 
Assessment 
 
 
X 
X 
X 
X 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
Previous and Concomitant 
Medications 
X 
 
X 
X 
X 
X 
X 
X 
Suicidal Behavior Questionnaire 
X 
 
 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 13 of 43 
 
 
• If the subject requires study approval from their own physician, the Investigational 
Product will be dispensed upon receipt of the signed authorization (Appendix 8) 
• Suicidal Behavior Questionnaire (Appendix 15) 
 
Screening/Baseline for the Remote Cohort – Visit 2 
• 
Urine pregnancy test for all females. This will be mailed to the participant after they 
have completed Screening/Baseline Visit 1. 
• Urine cotinine test. This will be mailed to the participant after they have completed 
Screening/Baseline Visit 1.  
• If subject meets all inclusion and exclusion criterion, a study ID will be assigned and 
he/she will be randomized in a 1:1:1 fashion to 1.0 mg b.i.d. varenicline, .5mg b.i.d. 
varenicline, or placebo. Participants and study staff will be blinded to the 
assignment.   
• Investigational Product educational information will be provided to participants 
• The Investigational Product will be dispensed to be used for the full 12 weeks of 
treatment 
• 
Participants will have 30 days from the start of their first screening visit to complete 
all the procedures and begin the medication 
• 
Participants will be asked to contact study staff when they receive the study 
medication to inform staff when they will be starting the medication so they 
remaining visits can be based on the medication start date. 
 
Week 2 Visit for the Remote Cohort 
• 
Minnesota Nicotine Withdrawal Scale  
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status and Resource Utilization Assessment (See Appendix 9) (Brief site 
administered questionnaires assessing smoking status, smoking cessation 
resources used since last study visit 
• 
Medication Adherence, and Perceived Efficacy Assessment (see Appendix 10) (Brief 
site administered questionnaires assessing pills taken since last study visit, and 
perceived efficacy of the medication.  
• 
Modified Cigarette Evaluation Questionnaire (mCEQ), see Appendix 11).  This 15-
item staff or subject administered questionnaire assesses the degree to which 
smokers experience the reinforcing effects of smoking.   
 
Week 4 Visit for Remote Cohort 
• 
Minnesota Nicotine Withdrawal Scale 
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Medication adherence and Perceived Efficacy Assessment 
• 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
 
Week 8 Visit for the Remote Cohort 
• 
Urine cotinine test, if they report not smoking 
• 
Minnesota Nicotine Withdrawal Scale 
• 
Adverse Events 
• 
Concomitant Medications 

Protocol #1R01DA044125  ver January 26, 2021              Page 14 of 43 
 
 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Medication adherence and Perceived Efficacy Assessment 
• 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
 
Week 12 for the Remote Cohort 
• 
Urine cotinine test, if they report not smoking 
• 
Minnesota Nicotine Withdrawal Scale 
• 
Adverse Events 
• 
Concomitant Medications 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Medication Adherence and Perceived Efficacy Assessment  
 
• 
Assess medication use by asking the participants to mail back any unused study 
medication 
• 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
 
Week 13 for the Remote Cohort 
• 
Smoking Status, and Resource Utilization Assessment  
• 
Adverse Events 
• 
Minnesota Nicotine Withdrawal Scale 
• 
Concomitant Medications including Chantix™ or other smoking cessation aids 
 
Week 26 for the Remote Cohort 
• 
Telephone call 
• 
Smoking Status and Resource Utilization Assessment  
• 
Urine cotinine test, if they report not smoking 
 
 
Visit Window for the Remote Cohort. Will be the same as shown in Table 2. 
 
 
 
Inclusion Criteria for the Remote Cohort 
1. 21 years of age or older 
2. Self-reported daily smoker 
3. Positive cotinine from urine sample 
4. Motivated to quit smoking completely within five weeks of the Screening Visit (>5 on 
reported motivation) 
5. Capable of and agree to complete study requirements 
6. Literate in English, self-report 
7. Must be available for the duration of study 
8. Informed consent obtained 
10. Must own study compatible smart-phone (iPhone or Android) 
11. Must be a current resident of the United States 
 
Exclusion Criteria for the Remote Cohort 
1. Any self-report, diagnosis or treatment of heart attack, unstable angina, 
angioedema, seizures, cerebrovascular accident (CVA) within the last six months. 

Protocol #1R01DA044125  ver January 26, 2021              Page 15 of 43 
 
 
2. Any self-report, diagnosis or treatment of bipolar, schizophrenia or suicidal ideation 
within the last six months. (For suicidal ideation a score of ≥7 on the Suicidal 
Behavior Questionnaire, see Appendix 15)   
3. Self-report of diagnosis or treatment for depression within the past six months, 
unless participant has written permission by their healthcare provider to participate  
4. History of renal disease 
 
5. Allergy to any of the ingredients in varenicline 
6. Participation in another smoking cessation program or any type of clinical trial in the 
past 3 months 
7. Use of any smoking cessation medication in the past three months 
8. Any other medical condition(s) which the licensed study physician deems 
unacceptable for participation in this study 
9. Consume greater than 21 alcohol drinks per week. 
10. No two members of the same household may participate in this study 
11. No study staff or their immediate family may participate in the study 
12. Females who are pregnant, breast feeding, or not currently using a medically 
approved form of birth control and unwilling to do so. 
Acceptable methods of birth control include abstinence, oral contraceptives, the 
contraceptive patch, the contraceptive ring, and condoms.  
 
Behavioral Support 
No behavioral support will be provided by the study team at any visit. At all follow-up 
visits post-randomization, they will not be given encouragement by study staff to quit 
smoking, nor be provided with any information or instruction about medication usage other 
than consent form and Chantix Use and Safety Information handout (see Appendix 12). We 
will assess at each visit whether subjects used any behavioral support available in the 
community. 
 
Risk/Benefit Assessment 
Risk Category. Greater than minimal risk 
Potential Risk. The most recent data found that varenicline does not result in 
greater risk than nicotine patch, which is already an over-the-counter medication, and that 
led the FDA to remove the box warning on varenicline.  The most common side effects of 
varenicline are: nausea, sleep problems (trouble sleeping, vivid, unusual, or strange 
dreams), constipation, and gas and/or vomiting, and there is a very small risk that a 
participant could develop an allergic reaction to varenicline. In addition, the product 
warnings indicate that: “Some people have had new or worse mental health problems, such 
as changes in behavior or thinking, aggression, hostility, agitation, depressed mood, or 
suicidal thoughts or actions while taking or after stopping varenicline. These symptoms 
happened more often in people who had a history of mental health problems. Some people 
have had seizures during treatment with varenicline. New or worse heart or blood vessel 
problems can happen with varenicline. Sleepwalking can happen with varenicline, and can 
sometimes lead to harmful behavior.31” 
Participants might also experience withdrawal symptoms from quitting smoking, 
including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, 
feeling anxious, difficulty concentrating, restlessness, decreased heart rate, increased 
appetite or weight gain. 
Protection Against Risks. Product information provided to participants will 
encourage them to use the product with a full glass of water after eating a meal.  The 
product information will encourage use caution when using machinery or driving, and to 

Protocol #1R01DA044125  ver January 26, 2021              Page 16 of 43 
 
 
decrease alcohol consumption. In addition, information on symptoms associated with an 
allergic reaction will be provided.  In addition, we will monitor participants at every visit to 
assess any potential adverse events, they will have a phone number that can be called at 
any time to contact study investigators, and they will be followed after they have 
discontinued medication to assess any effects for up to three months after medication 
completion. 
Potential Benefits to the Subjects. The potential benefits to participants are 
substantial because it could help them to quit smoking, which is the leading preventable 
cause of death in the US. 
Alternatives to Participation. Any of those who are not eligible for the study will be 
referred to the free smoking cessation quitline available in both states. In addition, any 
participants who elect to drop out of the study will also be referred to the state quitline, or 
could potentially obtain Chantix or another medication from their healthcare provider.   
 
Investigational Product 
 
Product: Varenicline (generic name, product name is Chantix™) 
 
Doses:  0.0 mg, .5mg and 1.0 mg 
 
Product Form:  Pill 
 
Product Administration: Oral, with water 
 
Manufacturer:  Pfizer 
 
Varenicline and Placebo. In this study, participants will be randomly assigned in 
double-blind fashion to use one of two doses of varenicline (.5 mg b.i.d. or 1.0mg b.i.d.) or 
placebo (see study design above). Both varenicline and the placebo will look identical and 
be in identical packaging.  
Medication Dosing. Participants assigned to the 1.0 mg b.i.d. condition, which is 
the current FDA-recommended dosing, will follow the recommended varenicline titrated 
dosing schedule as follows: days 1 through 3: 0.5mg, one daily; days 4 through 7: 0.5mg, 
twice daily; days 8 through end of treatment: 1mg, twice daily. Those assigned to the 0.5mg 
bid. condition will begin use 0.5mg once daily days 1 through 3, then will begin using 0.5 
b.i.d on day 4 through the end of the study.  Those assigned to the placebo condition will 
use pills that look identical to those that are being used in the other conditions but contain 
no medication.  The subjects in the placebo group will also titrate during the first 7 days (1 
pill days 1-3, 2 pills for the duration of the treatment period).  All participants will take 
identical looking pills at the same time throughout the study, with the only difference being 
the amount of varenicline included in each pill.   
Product Packaging. Medication packaging for this study will be implemented at the 
ASU site. Two study staff will work together to package the medications, and all packaging 
will be double checked and tracking forms maintained by the staff to assure quality control.  
Medications will be shipped by FedEx or equivalent to LACT (or directly to participants if 
they are participating in the study remotely), where study product will be checked and a 
report provided back to ASU within 24 hours indicating whether all sent medications were 
received.   
Product will be packaged for each in-person cohort study visit as follows: (1) 
Baseline to Week 4:  During the first week after baseline, when participants start and ramp 
up their dose, standard multi-compartment pill organizer containers will be provided to study 
participants with their assigned dosing regimen (as indicated above).  In addition, 
participants will be provided 28 days of their maintenance twice daily dose in a standard 
child resistant-pill bottle. This will allow for an extra 7 days of IP to account for delays in 
attending the Week 4 visit.  (2) Week 4 and Week 8:  Medication will be provided in a pill 

Protocol #1R01DA044125  ver January 26, 2021              Page 17 of 43 
 
 
bottle at each visit, and in order to assure adequate supply in case of a delay in study visits, 
each container will contain enough product to last 5 weeks.  All containers will be child-
resistant for added protection, and labeled appropriately for the study.   
Product will be packaged for the remote cohort as follows: product will be mailed 
after the second baseline visit. The first week of starting the medication, when participants 
start and ramp up their dose, standard 7-day multi-compartment pill organizer containers 
will be provided to study participants with their assigned dosing regimen (as indicated 
above).  In addition, participants will be provided 12 weeks of their maintenance twice daily 
dose in a standard child resistant-pill bottle. All containers will be child-resistant for added 
protection, and labeled appropriately for the study.   
Product Education Information. When participants are provided Investigational 
Product the first time (Screening/Baseline 1 or 2), they will be given a consumer-friendly 
handout, Chantix Use and Safety Information (Appendix 12) that includes information on 
how to use the medication, smoking cessation withdrawal symptoms, side effects and 
adverse events, and information on smoking cessation quitlines. This handout is a 
modification of the FDA-approved Chantix Medication Guide (Appendix 14), which was 
modified to meet needs of the study. The handout will include information on setting a quit 
date that exists on the Chantix™ website. The recommendation will be to set a quit date for 
Day 8 of medication use, or up to 30 days after starting the study product. Note that 
participants in all study conditions will have product available for a maximum of 12 weeks. If 
participants wish to use the medication beyond 12 weeks, they will need to contact their 
own health care provider for a prescription that they can fill at their own expense. We will 
assess at each follow-up visit whether any participants used varenicline beyond the 12 
weeks of this study. 
Blinding.  Our statistician will create the code that will allow identification of which 
numbered product is varenicline or placebo, and the code will be maintained in a sealed 
envelope in a locked cabinet by the ASU and LACT study sites that can be readily accessed 
in case of emergencies. 
Medication Cost. There will be no medication cost to participants. Because some of 
the participants will receive placebo, charging for the product would not be reasonable. In 
addition, this design is consistent with the approach approved by the FDA when testing NRT 
OTC studies, so we want to use a design that has potential relevance to the FDA.  
 
Adverse Events 
Handling Adverse Events. Multiple very large studies have demonstrated that 
varenicline has a safety profile that is very similar to NRT5. Clinical trials to date indicate that 
varenicline utilization results in very few serious adverse events. However, we will take 
tracking and management of adverse events very seriously (as we have in our previous 
studies). As indicated above, we will make sure to assess adverse events that might reflect 
exacerbation of any reported or unreported psychiatric disorders. 
Adverse Event (AE) Definitions. Any negative event subsequent to signing 
consent but prior to the week 13 visit will be considered a potential adverse event to be 
addressed and followed, regardless of whether it is related to use of study medication.  
Examples of AEs include: (1) Clinical signs and symptoms, (2) Abnormal test results, (3) 
Worsening of existing medical conditions. The licensed medical professional (LMP) will 
consider adverse events serious if the event: (1) is life threatening, (2) results in death, (3) 
leads to incapacity, hospitalization, or serious impairment of normal life, (4) congenital 
abnormality or birth defect.  Serious AEs will be reported to the IRB within 24 hours of the 
site becoming aware of the event.  Once an adverse or serious adverse event is identified, it 
must be followed and recorded, such that subsequent to the designation each event 

Protocol #1R01DA044125  ver January 26, 2021              Page 18 of 43 
 
 
outcome should be characterized as follows: 1 = Still present, 2 = Resolved with Sequelae, 
3 = Resolved without Sequelae, 4 = Lost to follow-up/Unknown, 5 = Death. 
Determination of Severity.  The study coordinators will make a determination of AE 
severity and provide a grade for each event according to the following criterion: Mild: 
Symptoms cause little discomfort, are easily tolerated, and do not significantly interfere with 
normal everyday activities. Moderate: Symptoms are uncomfortable and interfere with 
normal everyday activities. Severe: Symptoms cause significant impairment of everyday 
activities, incapacitation, or death 
Determination of Causality.  The LMP will make a determination the causality of 
each adverse event in relation to the study medication using the following criteria: 1 = 
Definite, 2 = Probable, 3 = Possible, 4 = Remote, 5 = Definitely Not 
Process for Handling AEs.  At each visit and post-cessation call (and via EMA, see 
sub-study below), every participant will be asked to report on health status and adverse 
events. In addition, study participants will be instructed verbally and in writing to contact the 
study staff immediately if any health problem causes disruption in the participant’s life – 
though participants will be informed to call 911 if they are experiencing any potentially life-
threatening problems. Calls to the study staff will be triaged to determine if the study LMP 
should be contacted. The Arizona State University and LACT study physicians will address 
any medical problems that might arise (including working with each participant’s health care 
provider if needed).   
AE Reporting Period. All events not resolved or unrecovered by week 13 will be 
followed for 30 days after that date to assess status.  Any participants lost to follow-up after 
a reported AE or serious AE will have ‘unknown’ indicated for that event. 
 
Participant Payment 
Main Study and Sub-studies. Note that all study participants will receive 
compensation for time and/or travel to the study sites as well as completing telephone visits 
during the treatment and follow-up study phases. Participants in the in-person cohort  will be 
paid $50 compensation for the screening/baseline visit, $25 compensation for completing 
each of the weeks 2 and 13 telephone visits, $50 for completing the in-clinic visits at weeks 
4 and 8, and $100 for completing the in-clinic week 12 visit (total of $250), regardless of 
their smoking status. In addition, study participants will be compensated $50 to come into 
the study sites to complete electronic questionnaires and to provide a breath CO if they 
report 7-day point prevalence abstinence at the 6-month follow-up call. Given the attrition 
that occurs in many smoking cessation studies, especially those that assess OTC 
medications, compensation for key study visits is essential.  
Participants in the Remote Cohort will be paid $50 combined for screening/baseline 
visits 1 and 2, $25 compensation for completing each of the weeks 2 and 13 visits, $50 for 
the visits at weeks 4 and 8, and $100 for completing the week 12 visit (total for $200), 
regardless of their smoking status. In addition, remote study participants will be 
compensated $50 electronic questionnaires and to provide a urine sample for cotinine 
analysis if they report 7-day point prevalence abstinence at the 6-month follow-up call. 
Compensation will be paid to participants electronically. 
Participants in the sub-studies will also be compensated. (1) EMA sub-study:  
Participants (total N = 75, or 25/medication condition) in the EMA sub-study will receive an 
additional $30 for completion of Week 1 EMA assessments and $40 for Week 2 EMA 
assessments. To encourage compliance with the EMA protocol and decrease incidence of 
missing data, sub-study participants will receive an additional $10 in Weeks 1 and 2 if they 
complete 6 of 7 daily diaries, and will receive an additional $10 in Weeks 1 and 2 if they 
respond to at least 3 scheduled prompts a day in each week. In total, EMA participants will 

Protocol #1R01DA044125  ver January 26, 2021              Page 19 of 43 
 
 
be compensated an additional $70 to $110 at the Week 4 visit, depending on protocol 
compliance.  
 
EMA Sub-Study 
Methods. We will randomly assign 25 people from each condition to participate in 
the EMA sub-study that lasts two weeks after the participants begin using varenicline, and 
they will be informed in the consent form at the Baseline/Screening visit that they may be 
asked to participate in the sub-study. We will use two types of EMA data assessments: (1) 
evening daily diaries to collect information on concrete behaviors (e.g., smoking and taking 
medication) that occurred that day, and (2) scheduled prompts to assess states (e.g. mood, 
craving, nausea) that fluctuate throughout the day (Appendix 13). Data will be collected 
using scheduled text messages linked to Qualtrics, which provides HIPPA-compliant data 
collection. At the Baseline/Screening visit, the research assistant will enroll substudy 
participants in the text message EMA data collection and will train participants how to 
respond to the scheduled prompts and the daily diary EMA surveys. The evening daily diary 
will include two brief questions on cigarette and varenicline pill consumption that day. In 
addition to the daily diary, participants will also respond to up to five scheduled prompts 
throughout the day. The first scheduled prompt will occur at 9am, and will include five brief 
questions on vivid dreaming and sleep quality from the last night, momentary nausea, 
momentary mood, and momentary craving. After the first scheduled prompt of the day is 
completed, subsequent scheduled prompts will ask about momentary nausea, mood, and 
craving only. Participants will be prompted to complete scheduled surveys at waking and at 
every four hours. Scheduled prompts will expire 30 minutes after their scheduled time; 
evening daily diaries can be completed any time after their scheduled time until midnight.  
 
EMA Data Collection Summary. Table 3 shows the information and frequency that 
will be collected via EMA. 
 
Table 3. EMA schedule of assessments. 
 
Baseline 
Week 
 
 
1 
2 
Assignment to EMA sub study 
X 
 
 
Subject review of Varenicline Label 
X 
 
 
 
 
 
 
Text message instructions 
X 
 
 
Scheduled prompts 
 
 
 
     Vivid dreaming (last night) 
 
X 
X 
     Sleep quality (last night) 
 
X 
X 
     Nausea (current) 
 
X 
X 
     Mood (current) 
 
X 
X 
     Cigarette craving (current) 
 
X 
X 
Daily diaries 
 
 
 
     Number of cigarettes smoked that 
day 
 
X 
X 
     Varenicline taken that day 
 
X 
X 
                 Additional thoughts/feelings? 
 
X 
X 
 
EMA compliance and feasibility. The EMA scheduled prompts and daily diary are 
extremely brief. Similar assessments from Dr. Pearson’s Moment Study took typical 

Protocol #1R01DA044125  ver January 26, 2021              Page 20 of 43 
 
 
participants no more than 90 seconds to complete. To reduce missing data, participants 
who miss more than two sequential days of evening daily diaries or complete fewer than 
three scheduled prompts a day for two sequential days will receive encouragement texts 
and calls from an RA to troubleshoot any problems with the app and encourage compliance.  
 
Definitions of Success 
FDA Abstinence Criteria. As indicated earlier, in all studies that assess medications for 
smoking cessation, the FDA typically requires verification of 28 days of continuous 
abstinence, i.e.; not a single puff from a single cigarette. The FDA does not require the 
‘clock’ to start at a consistent time point after study enrollment. Thus, in many studies the 
‘clock’ on that 28 days begins two weeks after study medication has begun, while in other 
studies the ‘clock’ starts at a different time point. In the current study, we will follow the 
protocol used in the varenicline pivotal trials.6,17-20 The primary study outcome in the 
proposed study will be continuous abstinence between weeks 8 and 12 after study 
medication has begun. Subjects who are randomized but who never obtain medication will 
be considered treatment failures and will be included in the denominator in the intent-to-
treat analyses. 
 
D. DATA SAFETY MONITORING PLAN 
Participant Safety. This study includes the use of a medication, varenicline, that is 
FDA-approved, as well as the same medication at a lower dose than approved by the FDA, 
in order to assess whether smokers can choose and use the medication without a 
healthcare provider prescription.  Given the existing data, the likelihood of participants 
experiencing a serious adverse event from the use of varenicline is very low.  In fact, in one 
of the largest smoking cessation studies ever conducted, the adverse events related to 
varenicline were similar to those from the nicotine patch, which is already approved as an 
OTC medication. 
However, we will monitor very carefully the screening and ongoing participation of all 
participants. Study participants will only be allowed to participate and receive medication if 
the study licensed healthcare provider at each site has approved their participation after 
reviewing screening documents. Regular visits as well as assessments between visits will 
provide updates on potential adverse events, and any serious events will be assessed 
(including for causality) by the study physicians and reported to Western IRB and the study 
sponsor (National Institute on Drug Abuse/NIH) within 24 hours.  
 
We will also identify an independent safety-monitoring panel (comprised of an MD 
and two additional scientists to be determined) who receive reports once a year on 
participant safety, protocol violations, medication use, and any other relevant topics in order 
to assure patient safety and study integrity. The safety-monitoring panel will assess all 
adverse events, and will make an independent recommendation on how study staff should 
address any concerns that they have raised.  Their report will be maintained in the study file 
notebook. 
 
E. DATA MANAGEMENT AND ANALYSIS 
Data Collection, Management and Storage. All participant data will be collected 
and stored on the password protected iPad, and all iPads will be maintained in accordance 
with Good Clinical Practices and FDA regulations, e.g. in locked cabinets in locked rooms 
with acess restricted only to study personnel. Once each month, data will be securely sent 
from LA Clinical Trials to the Arizona State University, where the data will be stored for 
analysis. We are currently implementing a different study together, and the data transfer has 
worked well.  

Protocol #1R01DA044125  ver January 26, 2021              Page 21 of 43 
 
 
Sample Size. The primary analysis of this study is to compare the quit rates 
between groups. The sample size estimation is based on the results from Oncken et al.6 the 
quit rates at 12 weeks for 0.5, 1.0 mg b.i.d. titrated groups and control group are 
approximately 45%, 60% and 15%. In an OTC setting, we assume the rates would reduce 
by half. Therefore, 23%, 30% and 8% are used to determine the sample size. Since we are 
interested in comparing the two active treatment arms with the control arm, to control for the 
overall type I error rate, the Bonferroni adjustment is applied: for each comparison, the type 
I error is 0.025. With 110 participants per group, we have at least 80% power to detect a 
difference of 23% vs. 8% (0.5mg vs. control) by the chi-square test. Even though a smaller 
sample size is required to detect a difference of 30% vs. 8% (1.0mg b.i.d. vs. control), we 
plan to enroll equal number of participants for each arm.  
For the EMA component of the study, we anticipate the primary outcomes for each 
treatment condition in the EMA subgroup will not be statistically different from the non-EMA 
sample and plan to analyze the primary outcomes based on the combined sample. 
However, the data collected will provide information to quantify the longitudinal within 
subject association. In particular, we hypothesize that the severity of side effect will increase 
in the first 5 days after the initiation of treatment, and expect the odds of side effect at day 5 
is three times the odds at day 1. Based on our simulations (type I error 0.05, 5 time points, 
and intra-class correlation 0.3), with 25 participants per group, we have at least 80% power 
to detect an odds ratio of 3. 
Data Sharing Plan. The information that we will collect includes medically-related 
information that is protected and must remain confidential, so all standard methods to 
protect participant confidentiality will be employed, including maintaining information in 
password protected encrypted databases to reduce the risk of a data breach. Shared data 
across the two study sites will likewise be password protected and encrypted. After study 
completion, any outside requests for data will require a data sharing agreement that assures 
the following: (1) all data must be maintained in a secure fashion using appropriate 
technology, (2) commitment to use the data only for the research purposes requested, and 
(3) all shared data must either be destroyed or returned, including written assurances to that 
effect.  
 
Statistical Analysis Plan  
Main study.  The participation flow will be reported following CONSORT guidelines. 
Intention to treat analysis will be applied for all statistical analyses. The data collected from 
the study will be summarized by the descriptive statistics for overall and by treatment 
condiction (1mg b.i.d., .5mg b.i.d. and placebo) and by the application of EMA (yes/no). The 
primary analysis will include estimating and comparing the quit rates between treatment 
arms. We will fit a logistic regression to model the probability of smoking cessation at 12 
weeks with treatment condition, application of EMA and the interaction term of the two main 
effects as independent variables. If the interaction term is not significant, this implies the quit 
rates for the same treatment condition are similar in those with and without the utilization of 
EMA, and we will drop the interaction term and fit a model with main effects only. The 
comparison will be perfromed by the Wald test from the logistic regression with Bonferroni 
adjustment to account for multiple comparisons. The point estimate of quit rate and 95% 
confidence interval (CI) for each treatment condition will be reported. If the interaction term 
is significant, we will conduct the comparisons in EMA and non-EMA subgroups. A similar 
approach will be applied to the analysis of adherence and adverse events. These two 
outcome variables can be analyzed as a dichotomous (yes/no) or count variable (pill count 
and number of adverse events), and the logistic regression and Poisson regression will be 
used to evaluate whether group differences occur. In the secondary analysis, to evaluate 

Protocol #1R01DA044125  ver January 26, 2021              Page 22 of 43 
 
 
the impact of participant characteristics on the study outcomes, we will fit multivariable 
logistic or Poisson regression models. The odds ratio (from logistic regression) and ratio or 
percent change (from Poisson regression) will be reported to quantify the association.  
In addition to evaluting the primary and secondary outcomes at the end of treatment 
(12 week), the trend over time between the initiation of treatment and at the end of the 
follow up period is also of interest. We will implement generalized linear mixed model 
(GLMM) with random intercept to account for the clustering effect (multiple visits clustered 
within each participant).32,33  Independent variables will include treatment condition, visit 
number, and other time-varying characteristics collected post radomization. We intend to 
use two-level GLMMs, and will perform exploratory analysis using 3-level GLMMs (visits 
clustered within participants, and participants clustered within sites [CA, AZ]), as we 
anticipate the variability from sites would be negligible. 
Analysis of the Remote Cohort.  We will assess the in-person and remote cohort 
data via separate analyses, but because the fundamental study design in the same for both, 
if the outcomes of the separate analyses suggest similar outcomes, we might combine the  
results of both groups into a single analysis. 
 
EMA Statistical Analysis Plan.  Our approach to analyzing EMA data is based on 
published approaches32,33 using GLMMs. This class of models is useful for analyzing EMA 
data because they allow multiple observations per subject, multiple levels of nesting (i.e., 
observations within weeks within subjects), multiple subject random effects, modeling of 
between-subjects (BS) and within-subjects (WS) variance as a function of time-invariant 
covariates (e.g. treatment assignment, gender, or nicotine dependence), and extension to 
non-normal outcomes (i.e., dichotomous, ordinal, counts). Our primary approach will be a 
three-level mixed model treating observations (level 1) within days (level 2) within subjects 
(level 3). Additionally, we will employ a time-varying effect model (TVEM)34 if we find 
evidence that the relative association between momentary medication adherence, side 
effects, craving, and smoking varies over the two weeks of observation.35 We present brief 
examples of analyses of central interest below. 
  
Our proposed EMA design allows for examination of multiple within-person, 
longitudinal associations between medication use, side effects, smoking, and craving, thus 
identifying the mechanisms driving smoking cessation when varenicline is used OTC. (1) 
The role of time on side effects: H1: Average ratings of day-level side effect severity (e.g. 
nausea, sleep disturbance, vivid dreams) will increase in the first week of varenicline use. 
H2: Average within-person change in side effects will be greatest for those in the 1mg b.i.d 
condition. (2) The role of side effects on medication adherence: H3: Average ratings of day-
level side effect severity will predict the odds of day-level medication adherence. (3) The 
role of medication adherence on momentary craving and smoking: H4: Day-level medication 
adherence will predict the day-level odds of smoking, mediated by average craving within-
person. H5: Day-level medication adherence will predict day-level craving similarly for those 
in the 1 mg b.i.d and 0.5 b.i.d. conditions, but not the placebo condition. 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 23 of 43 
 
 
F. REFERENCES 
 
1. Centers for Disease Control and Prevention. Tobacco-Related Mortality, 2015. 
2. Centers for Disease Control and Prevention. Comparative Causes of Annual Deaths in 
the United States, 2005. 
3. Centers for Disease Control and Prevention. Cigarette smoking among adults--United 
States, 2000. MMWR - Morbidity and Mortality Weekly Report 2002:642-25. 
4. Zhu S-H, Melcer T, Sun J, et al. Smoking cessation with and without assistance: A 
population-based analysis. Am J Prev Med 2000;18(4):305-11. 
5. Cinciripini PM, McClure JB. Smoking cessation: recent developments in behavioral and 
pharmacologic interventions. Oncology (Williston Park, NY) 1998;12(2):249-56, 59; 
discussion 60, 65, 2. 
6. Fiore M.C. BWC, Cohen S.J. et al. Treating tobacco use and dependence: Clinical 
practice guideline. In: Services UDoHaH, ed. Rockville, MD, 2000. 
7. Hughes JRG, M. Transdermal nicotine for smoking cessation. Health Values 1993;17:25-
31. 
8. Watts SA, Noble SL, Smith PO, et al. First-line pharmacotherapy for tobacco use and 
dependence. The Journal of the American Board of Family Practice 2002;15(6):489-97. 
9. Cummings KMH, A. Impact of Nicotine Replacement Therapy on Smoking Behavior. 
Annual Review of Public Health 2005;26(1):583-99. 
10. Hughes JR, Shiffman S, Callas P, et al. A meta-analysis of the efficacy of over-the-
counter nicotine replacement. Tobacco Control 2003;12(1):21-27. 
11. Leischow SJ, Nilsson, F., Franzon, M., Hill, A., Otte, P.S. & Merikle, E.P. Efficacy of the 
nicotine inhaler as an adjunct to smoking cessation. Am J Health Behav 1996;20(5):364-
71. 
12. Leischow SJ, Muramoto, M.L., Cook, G.N., Merikle, E.P., Castellini, S.M. & Otte PS. 
OTC nicotine patch: effectiveness alone and with brief physician intervention. Am J 
Health Behav 1999;23(1):61-69. 
13. Kotz D, Brown, J. & West, R. ‘Real-world’ effectiveness of smoking cessation 
treatments: a population study. Addiction 2014;109(3):491-99. 
14. Nides M, Glover ED, Reus VI, et al. Varenicline versus bupropion SR or placebo for 
smoking cessation: a pooled analysis. Am J Health Behav 2008;32(6):664-75. 
15. Cahill K, Stevens, S., Perera, R. & Lancaster, T. . Pharmacological interventions for 
smoking cessation: an overview and network meta-analysis. . Cochrane Database of 
Systematic Reviews 2013(5). 
16. Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination varenicline and bupropion sr 
for tobacco-dependence treatment in cigarette smokers: A randomized trial. Jama 
2014;311(2):155-63. 
17. Anthenelli RM, Benowitz, N. L., West, R., St Aubin, L., McRae, T., Lawrence, D., 
Ascher, J., Russ, C., Krishen, A., Evins, A. E. Neuropsychiatric safety and efficacy of 
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric 
disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. The 
Lancet 2016;387(10037):2507-20. 
18. Oncken C, Gonzales D, Nides M, et al. EFficacy and safety of the novel selective 
nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. 
Archives of Internal Medicine 2006;166(15):1571-77. 
19. Ebbert JO, Wyatt KD, Hays JT, et al. Varenicline for smoking cessation: efficacy, safety, 
and treatment recommendations. Patient preference and adherence 2010;4:355-62. 

Protocol #1R01DA044125  ver January 26, 2021              Page 24 of 43 
 
 
20. Brose LS, West R, Stapleton JA. Comparison of the effectiveness of varenicline and 
combination nicotine replacement therapy for smoking cessation in clinical practice. 
Mayo Clin Proc 2013;88(3):226-33. 
21. Kotz D, Brown, J. & West, R. Prospective cohort study of the effectiveness of varenicline 
versus nicotine replacement therapy for smoking cessation in the “real world”. BMC 
Public Health 2014;14(1):1-5. 
22. Coe JW, Brooks, P. R., Vetelino, M. G., Wirtz, M. C. & et al. Varenicline:  An α4β2 
Nicotinic Receptor Partial Agonist for Smoking Cessation. Journal of Medicinal 
Chemistry 2005;48(10):3474-77. 
23. Fagerström K, Gilljam H, Metcalfe M, et al. Stopping smokeless tobacco with 
varenicline: randomised double blind placebo controlled trial. Bmj 2010;341. 
24. Chantix™ TM. (Varenicline tartrate) Prescribing Information. In: TM C, ed., 2006. 
25. Pasternak B, Svanström, H. & Hviid, A. Use of varenicline versus bupropion and risk of 
psychiatric adverse events. Addiction 2013;108(7):1336-43. 
26. Gibbons RDM, J.J. Varenicline, Smoking Cessation, and Neuropsychiatric Adverse 
Events. American Journal of Psychiatry 2013;170(12):1460-67. 
27. Thomas KH, Martin, R. M., Knipe, D. W., Higgins, J. P. T. & Gunnell, D. Risk of 
neuropsychiatric adverse events associated with varenicline: systematic review and 
meta-analysis. Bmj 2015;350. 
28. Molero Y, Lichtenstein, P., Zetterqvist, J., Gumpert, C. H. & Fazel, S. Varenicline and 
risk of psychiatric conditions, suicidal behaviour, criminal offending, and transport 
accidents and offences: population based cohort study. BMJ 2015;350. 
29. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective 
alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, 
placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 
2006;166(15):1561-8. 
30. 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. 
31. Medication Guide Chantix: https://www.pfizermedicalinformation.com/en-
us/chantix/medguide 
32. Hedeker D, Mermelstein RJ, Demirtas H. Modeling between-subject and within-subject 
variances in ecological momentary assessment data using mixed-effects location scale 
models. Statistics in medicine 2012;31(27):3328-36. 
33. Hedeker D, Mermelstein RJ, Demirtas H. An Application of a Mixed-Effects Location 
Scale Model for Analysis of Ecological Momentary Assessment (EMA) Data. Biometrics 
2008;64(2):627-34. 
34. Yang J, Tan, X., Li, R., & Wagner, A. . TVEM (time varying effect model) SAS macro 
suite users’ guide (version 2.0.0). . University Park, PA: The Methodolgy Center, Penn 
2012. 
35. Vasilenko SA, Piper ME, Lanza ST, et al. Time-varying processes involved in smoking 
lapse in a randomized trial of smoking cessation therapies. Nicotine Tob Res 2014;16 
Suppl 2:S135-43. 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 25 of 43 
 
 
G. Appendix  
 
 
Appendix 1 
 
 
Demographic Information  
1. Gender ________   
2. DOB:  _________________    
3. Race (Check all that apply):  
White or Caucasian _____   
Black or African American _____   
Asian_____   
Native Hawaiian or other Pacific Islander _____   
American Indian or Alaska Native_____   
Other______________________  (specify)   
 
4. Ethnicity:  
Hispanic_____ 
Non-Hispanic_____   
 
5. Highest Level of Education 
Some high school or less_____ 
High school graduate or GED_____ 
Some college, no degree_____ 
Associate’s degree_____ 
Bachelor’s degree_____ 
Graduate degree_____ 
 
 
 
 
 
 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 26 of 43 
 
 
 
 Appendix 2 
Nicotine Use History Questionnaire 
 
1. 
Average number of cigarettes smoked per day during the past 3 months? _____ 
a. 
What brand do you smoke?_____________  
b. 
What size (mm) _______ (70, 72,84, 100,120, other: specify, not applicable) 
c. 
Menthol or tobacco flavor?________   
i.Full flavor_____  Medium____ Light____  Ultralight__________ 
ii.Package color______________________________ 
iii.Filter____ Non filter____  
iv.Commercially rolled______ roll your own_____  
2. 
Age started smoking?  ______  
3. 
Maximum CPD smoked on average during any one year since started smoking? _____ 
4. 
Number of serious quit attempts? _____ 
5. 
If >0: 
a. 
 Longest time quit smoking?  Years____ Months_____ Days_____ 
b. 
Methods used to quit smoking: 
i.Counseling    
 
Yes____ No____ 
ii.Nicotine gum  
 
Yes____ No____ 
iii.Nicotine lozenge  
 
Yes____ No____ 
iv.Nicotine patch  
 
Yes____ No____ 
v.Nicotine Inhaler  
 
Yes____ No____ 
vi.Nicotine nasal spray  
Yes____ No____ 
vii.Chantix  
 
 
Yes____ No____ 
viii.Zyban  
 
 
Yes____ No____ 
ix.Electronic Cigarette  
Yes____ No____ 
6. 
How many other smokers in your household?___________ 
7. 
Other tobacco products used 
a. 
Ecigarettes/vape 
 
Yes____ No____ 
b. 
Hookah 
 
 
Yes____ No____ 
c. 
Cigars  
 
 
Yes____ No____ 
d. 
Smokeless tobacco  
Yes____ No____ 
e. 
Other (please specify:____________________________________) 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 27 of 43 
 
 
 
Appendix 3 
REALM Questionnaire 
RAPID ESTIMATE OF ADULT LITERACY IN MEDICINE (REALM)© 
                 List 1 
                    List 2 
                       List 3 
 
Correc
t 
Not 
Corre
ct 
 
Correc
t 
Not 
Correc
t 
 
Correc
t 
Not 
Correc
t 
Fat 
 
 
fatigue 
 
 
allergic 
 
 
Flu 
 
 
pelvic 
 
 
menstrual 
 
 
Pill 
 
 
jaundice 
 
 
testicle 
 
 
Dose 
 
 
infection 
 
 
colitis 
 
 
Eye 
 
 
exercise 
 
 
emergency 
 
 
Stress 
 
 
behavior 
 
 
medication 
 
 
Smear 
 
 
prescription 
 
 
occupation 
 
 
Nerves 
 
 
notify 
 
 
sexually 
 
 
Germs 
 
 
gallbladder 
 
 
alcoholism 
 
 
Meals 
 
 
calories 
 
 
irritation 
 
 
disease 
 
 
depression 
 
 
constipation 
 
 
cancer 
 
 
miscarriage 
 
 
gonorrhea 
 
 
caffeine 
 
 
pregnancy 
 
 
inflammatory 
 
 
Attack 
 
 
arthritis 
 
 
diabetes 
 
 
Kidney 
 
 
nutrition 
 
 
hepatitis 
 
 
hormones 
 
 
menopause 
 
 
antibiotics 
 
 
Herpes 
 
 
appendix 
 
 
diagnosis 
 
 
seizure 
 
 
abnormal 
 
 
potassium 
 
 
Bowel 
 
 
syphilis 
 
 
anemia 
 
 
asthma 
 
 
hemorrhoids 
 
 
obesity 
 
 
Rectal 
 
 
nausea 
 
 
osteoporosis 
 
 
Incest 
 
 
directed 
 
 
impetigo 
 
 
 
 
Total Score: _____________of 66 correct. 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 28 of 43 
 
 
 Appendix 4 
Minnesota Nicotine Withdrawal Scale (MNWS) 
 
 
 
MNWS 
Please answer the questions based on how you have felt or what you have noticed in the past week. 
Answer based on how you have felt in general during this time.  Please indicate with an X in the 
applicable box. 
None 
Slight 
Mild 
Moderate 
Severe 
1) Angry, irritable, frustrated
2) Anxious, nervous
3) Depressed mood, sad
4) Desire or craving to smoke
5) Difficulty concentrating
6) Increased appetite, hungry, weight gain
7) Insomnia, sleep problems, awakening at night
8) Restless
9) Impatient
10) Constipation
11) Dizziness
12) Coughing
13) Dreaming or nightmares
14) Nausea
15) Sore throat

Protocol #1R01DA044125  ver January 26, 2021              Page 29 of 43 
 
 
  
Arizona State University 
School of Nutrition and Health Promotion 
Healthy Lifestyles Research Center 
DATE                                                                                  Study Name:  Varenicline OTC Trial on Efficacy and Safety                 
 
This letter is to communicate the results of a recent measurement of your blood pressure.  
 
Your blood pressure today was _____(systolic)  /_____ (diastolic) 
 
The results obtained are outside of the normal range. We recommend you share and discuss 
these results with your primary care physician or qualified healthcare provider within 5 days or within 
24 hours if your blood pressure is above 180 systolic or 120 diastolic. 
Below are local options for you to consider for access to care if you do not currently have a primary care provider: 
Emergency Rooms: 
St. Joseph's Hospital & Medical Center                                        Banner - University Medical Center Phoenix  
350 West Thomas Rd                                                                   1111 E. McDowell Rd 
Phoenix, AZ 85013                                                                       Phoenix, AZ 85006 
(602) 406-3000                                                                             (602) 839-2000 
https://dignity.inquicker.com/next-24/az/phoenix                          https://www.clockwisemd.com/hospitals/3253/appointments/new 
 
Urgent Care: 
Banner Urgent Care                                                                     Banner Urgent Care 
Camelback & 7th St                                                                      Indian School & 32nd St 
5018 N 7th St                                                                               3141 E Indian School Rd #102  
Phoenix, AZ 85014                                                                       Phoenix, AZ 85016 
(602) 255-7680                                                                             (602) 255-7700 
https://urgentcare.bannerhealth.com/ 
 
The results do not serve as definitive indicator of health or disease, and as the results of any test need to be evaluated in the context of 
other factors by a physician or clinician.  Therefore, these results do not serve as a diagnosis of any kind for any medical condition and 
need to be interpreted by a physician or qualified health care provider.  By signing below, you agree to share this information with your 
primary care physician to learn about how these results are relevant to your health and/or disease risk and discuss next steps. 
 
Research Results Acknowledgement Statement 
Read and initial each statement below and sign to request your research results: 
I understand that test results obtained during research studies are not used for diagnostic purposes.  
I understand that it is my responsibility to discuss any results and follow up with my primary care physician or 
qualified health professional and that neither the study investigator nor research staff will provide interpretation, 
counseling, consultation, or care recommendations on the basis of any of the research results provided to me. I 
release from liability and will not hold Arizona State University or the study physician responsible if I do not 
promptly communicate the results of these tests to my physician. 
My signature below confirms the above statements and receipt of my results from participation in the research study entitled: 
 
 
 
 
 
 
 
                   
 
 
 
 
 
Signature  
 
 
 
 
 
 
  Date 
 
 
 
 
 
 
 
 
                   
Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    Researcher collecting signature 
 
 
 
 
 
  Date 
 
 
 
 
 
 
 
 
                                 
 
 
 
                   
                                 Printed Name            
 
 
 
                                  Phone Number 
 
Appendix 5 

Protocol #1R01DA044125  ver January 26, 2021              Page 30 of 43 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 31 of 43 
 
 
 
 
 
Los Angeles Clinical Trials 
847 North Hollywood Way, Suite 103 
Burbank, CA 91505 818-526-7645 
DATE:_____________________________ 
Study Name:  Varenicline OTC Trial on Efficacy and Safety 
This letter is to communicate the results of a recent measurement of your blood pressure.  
Your blood pressure today was _____(systolic)  /_____ (diastolic) 
The results obtained are outside of the normal range. We recommend you share and discuss these results 
with your primary care physician or qualified healthcare provider within 5 days or within 24 hours if your blood pressure is 
above 180 systolic or 120 diastolic.  
Providence St. Joseph’s Medical Center is an option for you to consider for access to care if you do 
not currently have a primary care provider: It is approximately 2 miles from our clinic.   
Providence Saint Joseph Medical Center 
501 S. Buena Vista Street  
Burbank, CA 91505 
818-843-5111 
 
The results do not serve as definitive indicator of health or disease, and as the results of any test need to be evaluated in the context of 
other factors by a physician or clinician.  Therefore, these results do not serve as a diagnosis of any kind for any medical condition and 
need to be interpreted by a physician or qualified health care provider.  By signing below, you agree to share this information with your 
primary care physician to learn about how these results are relevant to your health and/or disease risk and discuss next steps. 
 
Research Results Acknowledgement Statement 
Read and initial each statement below and sign to request your research results: 
I understand that test results obtained during research studies are not used for diagnostic purposes.  
I understand that it is my responsibility to discuss any results and follow up with my primary care physician or 
qualified health professional and that neither the study investigator nor research staff will provide interpretation, 
counseling, consultation, or care recommendations on the basis of any of the research results provided to me. I 
release from liability and will not hold Arizona State University or the study physician responsible if I do not 
promptly communicate the results of these tests to my physician. 
My signature below confirms the above statements and receipt of my results from participation in the research study 
entitled: 
 
 
 
 
 
 
 
                   
 
 
 
 
 
Signature  
 
 
 
 
 
 
  Date 
 
 
 
 
 
 
 
 
                   
Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    Researcher collecting signature 
 
 
 
 
 
  Date 
 
 
 
 
 
 
 
 
                                 
 
 
 
                   
                                 Printed Name            
 
 
 
                                  Phone Number 
 
 
 
Appendix 6 

Protocol #1R01DA044125  ver January 26, 2021              Page 32 of 43 
 
 
MY BLOOD PRESSURE MEASUREMENT TODAY: 
DATE:  
 
 
 
BP:  
 
 
 
 
The 5 blood pressure ranges recognized by the American Heart Association are:  
Blood Pressure Category 
Systolic mm Hg 
(upper number) 
 
Diastolic mm 
Hg 
(lower number) 
 
NORMAL 
 
 
LESS THAN 12O 
 
and 
 
LESS THAN 80 
 
ELEVATED 
 
 
120-129 
 
and 
 
LESS THAN 80 
 
HIGH BLOOD PRESSURE 
(HYPERTENSION) 
STAGE 1 
 
 
130-139 
 
or 
 
80-89 
 
HIGH BLOOD PRESSURE 
(HYPERTENSION) 
STAGE 2 
 
 
140 OR HIGHER 
 
or 
 
90 OR HIGHER 
 
HIGH BLOOD PRESSURE 
(HYPERTENSION) CRISIS 
 
 
HIGHER THAN 180 
 
and/or 
 
 
HIGHER THAN 
120 
We provide this as a resource.  
It is important to manage your blood pressure at a healthy level. 
 
If your blood pressure is higher than 180/120 mm Hg and you are experiencing signs of 
possible organ damage such as chest pain, shortness of breath, back pain, 
numbness/weakness, change in vision, difficulty speaking, do not wait to see if your pressure 
comes down on its own.  
Call 9-1-1 
 
 
For more information about blood pressure contact the American Heart Association: 
WWW.Heart.org 
 
 
 
 
 
 
Appendix 7 

Protocol #1R01DA044125  ver January 26, 2021              Page 33 of 43 
 
 
 
 
Fagerström Test for Cigarette Dependence 
 
 
For each statement, circle the most appropriate letter that best describes you. 
 
1. How many cigarettes do you smoke per day? 
a) 10 or less 
b) 11 – 20 
c) 21 – 30 
d) 31 or more 
 
2. How soon after you wake up do you smoke your first cigarette? 
a) 0 – 5 min 
b) 6 – 30 min 
c) 31 – 60 min 
d) After 60 min 
 
3. Do you find it difficult to refrain from smoking in places where smoking is not allowed (e.g. 
hospitals, government offices, cinemas, libraries etc)? 
a) Yes 
b) No 
 
4. Do you smoke more during the first hours after waking than during the rest of the day? 
a) Yes 
b) No 
 
5. Which cigarette would you be the most unwilling to give up? 
a) First in the morning 
b) Any of the others 
 
6. Do you smoke even when you are very ill? 
a) Yes 
b) No 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 34 of 43 
 
 
Appendix 8 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 35 of 43 
 
 
 
 
Appendix 9 
Modified Cigarette Evaluation Questionnaire (mCEQ)⁎ 
 
If you have smoked since you last completed this questionnaire, please mark the number that 
best represents how smoking made you feel. 
 
(1—not at all, 2—very little, 3—a little, 4—moderately, 5—a lot, 6—quite a lot, 7—extremely). 
 
1. _______Was smoking satisfying? 
2._______ Did cigarettes taste good? 
3. _______Did you enjoy the sensations in your throat and chest? 
4. _______Did smoking calm you down? 
5. _______Did smoking make you feel more awake? 
6. _______Did smoking make you feel less irritable? 
7._______ Did smoking help you concentrate? 
8. _______Did smoking reduce your hunger for food? 
9. _______Did smoking make you dizzy? 
10. ______Did smoking make you nauseous? 
11. ______Did smoking immediately relieve your craving for a cigarette? 
12. ______Did you enjoy smoking? 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 36 of 43 
 
 
 
 
Appendix 10 
 
Smoking Status and Resource Utilization  
 
Smoking status 
At all visits 
1. Did you smoke any cigarettes, even a puff, since your last visit?   Yes   No 
2. [If Yes to 1] Did you smoke any cigarettes, even a puff, in the last 7 days?   
 
It has been approximately   ___________ weeks since your last visit.   
3. On approximately how many days did you smoke?   
 
 
4. On the days that you smoked, what is the average number of cigarettes that you 
smoked?   
 
 
Resource utilization 
At all visits 
a. Since your last visit, which of the following additional things have you tried to reduce 
or quit smoking? Check all that apply. 
 
a) A pamphlet or book 
b) Individual or group counseling  
c) Telephone counseling / quitline 
d) Nicotine patch, gum, nasal spray, lozenge, or inhaler 
e) E-cigarettes 
f) Zyban / bupropion 
g) Switching to chewing tobacco or snuff  
h) Switching brands  
i) 
Cutting back  
j) 
An Internet quit smoking program  
k) Alternative methods like herbs, lasers, homeopathic medicines, prayer, acupuncture, 
or hypnosis 
l) 
Something else: _________________________ 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 37 of 43 
 
 
Appendix 11 
 
Medication compliance and perceived efficacy  
 
Medication efficacy and compliance 
At all visits 
5. This medication is helping me/has helped me quit smoking. 
 
a) Strongly disagree 
b) Somewhat disagree 
c) Neither agree nor disagree 
d) Somewhat agree 
e) Strongly agree 
f) Don’t know  
 
At Week 2 telephone call only 
a. It has been ______days since your last visit.  After the first 3 days of taking the study 
medication the instructions were to take 2 pills per day. Approximately what percentage of 
days did you take:  
i. _________two doses per day 
ii. _________one dose per day 
iii. _________no doses 
 
 
 
At the Week 4, 8 and 12 visits 
6. It has been  ___________ number of days since your last visit. 
 
Approximately what percentage of days did you take:  
_________two doses per day 
_________one dose per day 
_________no doses 
 
Ask #7 only if any study product was reported as not used as recommended 
7. Main reason for not using medication as recommended (check only one): 
_______forgot 
_______side effect 
_______not working 
_______don’t need 
_______other    Specify: 
 
 
 
 
 
 
 
 
 
At Week 12 visit only 
8. Do you think you got the real drug or the placebo (fake drug) in this study? 
a. Real drug 
b. Placebo/fake drug 
c. Don’t know  
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 38 of 43 
 
 
Appendix 12 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 39 of 43 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 40 of 43 
 
 
 
 Appendix 13 
 
EMA Items for Scheduled Prompts  
 
Items for first scheduled prompt of the day 
 
1. How good did you sleep last night? 
a. Very bad 
b. Bad 
c. Ok 
d. Good  
e. Very good 
2. Did you have any unusually vivid, realistic, or crazy dreams last night?  
a. Yes 
b. No 
3. How nauseous do you feel right now? 
a. Not at all 
b. A little 
c. Somewhat 
d. A lot 
e. Extremely 
4. How is your mood right now? 
a. Very bad 
b. Bad 
c. Ok 
d. Good  
e. Very good 
5. How much do you want to smoke a cigarette right now? 
a. Not at all 
b. A little 
c. Somewhat 
d. A lot 
e. Very, very much 
 
 
 
Items for the remaining scheduled prompts of the day 
 
1. How nauseous do you feel right now? 
a. Not at all 
b. A little 
c. Somewhat 
d. A lot 
e. Extremely 
2. How is your mood right now? 
a. Very bad 
b. Bad 

Protocol #1R01DA044125  ver January 26, 2021              Page 41 of 43 
 
 
c. Ok 
d. Good  
e. Very good 
3. How much do you want to smoke a cigarette right now? 
a. Not at all 
b. A little 
c. Somewhat 
d. A lot 
e. Very, very much 
 
 
EMA Items for Evening Daily Diaries 
 
1. How many cigarettes did you smoke today? 
a. [Drop down menu, 0-60+] 
2. How many study pills did you take today? 
a. 0 
b. 1  
3. Any other thoughts or feelings that you want to tell us about? 
a. [open response] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 42 of 43 
 
 
 
Appendix 14 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 43 of 43 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 44 of 43 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 45 of 43 
 
 
 
 

Protocol #1R01DA044125  ver January 26, 2021              Page 46 of 43 
 
 
Appendix #15 
Suicidal Behaviors Questionnaire-Revised (SBQ-R) 
The Suicidal Behaviors Questionnaire-Revised (SBQ-R) provides a broad range of information in a brief 
administration. Responses can be used to identify at-risk individuals and specific risk behaviors. This 
questionnaire must be completed by all potential study subjects during screening. A score >7 indicates potential 
for suicidal ideation and would confirm study exclusion criteria #6. Copies of this questionnaire and details for 
interpretation and scoring will be provided in the study Procedure Manual and completed questionnaires must 
be present as source documents. Any subject meeting this exclusion must be followed by the clinical site 
according to site policies.  
 
1. Have you ever thought about or attempted to kill yourself? (check one only) 
□ 1.  Never 
□ 2.  It was just a brief passing thought 
□ 3a.  I have had a plan at least once to kill myself but did not try to do it 
□ 3b.  I have had a plan at least once to kill myself and really wanted to die 
□ 4a.  I have attempted to kill myself, but did not want to die 
□ 4b.  I have attempted to kill myself, and really hoped to die 
2. How often have you thought about killing yourself in the past year? (check one only) 
□ 1.  Never 
□ 2.  Rarely (1 time) 
□ 3.  Sometimes (2 times) 
□ 4.  Often (3-4 times) 
□ 5.  Very Often (5 or more times) 
3. Have you ever told someone that you were going to commit suicide, or that you might do it? (check 
one only) 
□ 1.  No 
□ 2a.  Yes, at one time, but did not really want to die 
□ 2b.  Yes, at one time, and really wanted to die 
□ 3a.  Yes, more than once, but did not want to do it 
□ 3b.  Yes, more than once, and really wanted to do it 
4. How likely is it that you will attempt suicide someday? (check one only) 
□ 0.  Never 
□ 1.  No chance at all 
□ 2.  Rather unlikely 
□ 3.  Unlikely 
□ 4.  Likely 
□ 5.  Rather likely 
□ 6.  Very likely