Measuring Neuroadaptations in Response to Very Low Nicotine Content Cigarettes
Phase: NA
Conditions: Tobacco Dependence
Sponsor: Milton S. Hershey Medical Center

Page 1 of 31 (V.04/27/2017) 
 
 
 
HRP-592 - Protocol for Human Subject  
Research with Use of Test Article(s) 
 
Protocol Title: 
Measuring Neuroadaptations in Response to Very Low Nicotine Content Cigarettes 
 
Principal Investigator: 
Name: Andrea Hobkirk  
Department: Psychiatry 
Telephone: 717-531-0003 ext. 286415 
E-mail Address: ahobkirk@pennstatehealth.psu.edu 
 
Version Date: 
9/20/2023 
 
Clinicaltrials.gov Registration #: 
NCT03612960 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 

Page 3 of 31 (V.04/27/2017) 
1.0 
Objectives 
 
1.1 
Study Objectives 
 
The specific aims of the current study are to: 
 
1) Examine the longitudinal effect of very low nicotine content (VLNC) cigarettes on changes in task-
related functional neural activation within brain circuitry associated with incentive salience valuation 
and executive function. We hypothesize that, for the VLNC group compared to the normal nicotine 
content (NNC) group:  
a. Reactivity to smoking vs. pleasant odors within incentive salience circuitry will decrease. 
b. Reactivity to monetary rewards within incentive salience circuitry will increase.  
c. Activity during decision-making and inhibitory control within executive control circuitry will 
increase. 
 
2) Assess the longitudinal effect of VLNC cigarettes on changes in effective (directional) connectivity 
between incentive salience and executive control brain circuitry. We hypothesize that, for the VLNC 
group compared to the NNC group:  
a. The influence of executive control over incentive salience circuitry, measured during task 
demands that simultaneously engage both processes, will increase.  
b. The influence of non-smoking reward salience circuitry over smoking salience circuitry during 
the odor cue reactivity task will increase.  
 
3) Establish measurable and objective neural outcomes of successful reductions in smoking 
dependence.  
1. We hypothesize that changes in functional activation and effective connectivity over the course 
of the VLNC intervention will be correlated with reductions in subjective and behavioral 
assessments of smoking dependence, including the number of cigarettes smoked per day, 
subjective reports of dependence, craving, and withdrawal. 
 
4) Assess the effect of VLN Cigarettes vs NNC cigarettes on the levels of salivary miRNAs targeting 
dopamine, glutamate, acetylcholine and GABA-related transcripts over 6-weeks. 
1. We hypothesize that the VLNC group will have significantly more changes in miRNA 
expression than the NNC group. A two-way repeated measures ANOVA will be conducted to 
compare changes in miRNA expression over three time points for the VLNC and NNC groups. 
 
5) Determine if within-subject changes in miRNA expression are associated with changes in fMRI 
BOLD signal during smoking cue-reactivity and inhibitory control tasks for the VLNC group over 6-
weeks.  
1. We hypothesize that salivary levels of miRNAs with putative targets in the nicotine addiction 
pathway will be associated with decreased corticostriatal cue-reactivity and increased 
ventromedial and dorsolateral prefrontal cortex engagement during inhibitory control in the 
VLNC group compared to the NNC group.  
 
1.2 
Primary Study Endpoints 
Changes in neural reactivity to tobacco odor and changes in smoking dependence. 
 
1.3 
Secondary Study Endpoints 
N/A 
 
2.0 
Background 
 

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2.1 
Scientific Background and Gaps 
Although half of the 37 million adult smokers in the US attempt to quit each year, only an estimated 3% 
are successful.1,2 This is why smoking continues to be the leading cause of preventable death in the US, 
killing nearly half a million people each year from tobacco-related causes.3 Given that approximately 
70% of smokers report a desire to quit, there is a critical need for improved neuropharmacological 
cessation aids to assist current smokers in quitting and to inform FDA regulations aimed at preventing 
highly addictive tobacco products from reaching the market.2 
A key neurobehavioral component that contributes to the development of cigarette addiction is the 
conditioned associations that form between smoking stimuli and the rewarding dopaminergic effects of 
nicotine.4 Associative learning is driven primarily by cellular and circuit-level changes in the 
mesocorticolimbic (e.g., hippocampus, amygdala, nucleus accumbens) and prefrontal brain structures.4,5 
Associations between stimuli and nicotine are strengthened with each puff of a cigarette.4 Ultimately, 
sensory smoking cues trigger positive expectancies of smoking and contribute to their high addictive 
potential.6 In other words, the salience of these smoking cues becomes heightened. This is why non-
nicotine factors significantly contribute to cigarette dependence.6,7 Animal research has shown that 
nicotine-associated cues can impede cessation even with pharmacological treatment.8 Using fMRI, 
blood-oxygen-level-dependent (BOLD) reactivity to nicotine-associated smoking stimuli has been linked 
to less control over cravings9, reductions in withdrawal symptoms10, and increased ad lib smoking during 
laboratory tasks.11 We currently have a limited understanding of how the salience of smoking cues, 
measured via cue-reactivity, is affected by tobacco products varying in nicotine content the use of 
cessation aids. 
While the salience of smoking cues increase for dependent smokers, the salience of non-smoking 
incentives, such as money, food, and socioemotional stimuli, is diminished.12 This is evident by smokers’ 
attenuated neural reactivity to the anticipation and receipt of monetary and food rewards during 
laboratory tasks compared to non-smokers.13-15 In addition, smokers show executive dysfunction in 
sustained attention, working memory, and inhibitory control processes during acute abstinence that are 
integral to maintaining goal-directed behavior during withdrawal.16-20 Executive control brain circuitry 
primarily includes the lateral and medial prefrontal cortex, anterior cingulate (ACC), superior and 
inferior parietal cortices, and in some cases subcortical structures.21 There is considerable overlap and 
communication between the circuitry involved in executive control and incentive salience valuation.22-24 
Impairments in inhibitory control and working memory have been associated with relapse during quit 
attempts25,26 and nicotine replacement therapy alleviates executive dysfunctions during withdrawal.27 
We are just beginning to understand how the circuitry underlying incentive salience and executive 
control work together to influence smoking dependence and treatment outcomes.13,28,29  
We currently know little about how neural activity and connectivity of the incentive salience and 
executive control circuitry change during cessation treatment. Given the advancements in 
pharmacotherapy and non-invasive brain stimulation techniques,30,31 gaining a nuanced understanding 
of how brain circuitry adapts during rehabilitation could identify neural targets for treatment. 
Verenicline and bupropion treatment are associated with reductions in neural activity throughout 
prefrontal brain circuitry during executive control and cue-reactivity tasks, respectively.32,33 However, 
given the reductions in dependence for the control groups, these neural changes were likely due to the 
effects of the medication, not changes in dependence.32,33 Very low nicotine content (VLNC) cigarettes 
have been used as an extinction-based cessation treatment to reduce the rewarding effects of cigarettes 
by significantly reducing nicotine delivery during smoking.6,34 Smokers rate de-nicotinized cigarettes as 
satisfying and trials of VLNC cigarettes result in decreases in the number of cigarettes smoked per day 
and self-reported dependence.35 VLNC cigarettes provide a unique opportunity to assess changes in 
neural circuitry while smokers extinguish the association between nicotine and smoking stimuli and 
become less dependent on smoking without the confounding effects of nicotine replacement therapy or 
pharmacotherapy.   
The current study will examine functional neuroadaptations in incentive salience and executive control 
circuitry while smokers switch to VLNC cigarettes over 6-weeks. Identifying brain circuitry that is 

Page 5 of 31 (V.04/27/2017) 
modified at various stages of recovery can lead to the development of targeted neuropharmacological 
cessation aids and brain stimulation techniques. The findings of the proposed study will characterize 
changes associated with the extinction of conditioned cues and reductions in dependence without the 
confounding effects of pharmacological aids. By measuring neural processes and connectivity among 
circuitry mid-intervention, the results of the proposed study will pinpoint aspects of neural circuitry that 
are sensitive to (or reflective of) early intervention effects. 
2.2 
Previous Data 
The Penn State Center for NMR Research (CNMRR) has pioneered the study of human olfaction, 
including circuitry involved in the detection and perception of odor36 and links to motivation, learning, 
and reward.37,38 Dr. Yang’s mentee, Dr. Cortese, conducted preliminary work showing that the scent of 
fresh tobacco induced higher subjective craving and skin conductance compared to a no-odor control 
condition.39 Using fMRI, pairing smoking odor and visual cues significantly enhanced cue-reactivity 
throughout frontal and temporal cortices, which was linked to control over craving.9 The proposed study 
will extend Dr. Cortese’s preliminary work by examining how smoke flavor (i.e., odor and taste) is 
modified by intervention and associated with dependence and cessation outcomes. 
 
In preliminary work conducted by the Penn State Tobacco Center of Regulatory Science (TCORS) we 
found that resting state functional connectivity decreased in key regions involved in executive control 
(frontal pole), reward valuation (anterior cingulate) and craving (insula and thalamus) after nicotine 
administration with an e-cig.40 Weaker coupling between reward and executive control networks was 
associated with less craving after use.40 This cross-sectional pilot study demonstrated that flavored 
electronic cigarettes altered brain connectivity among brain regions involved in the development of 
smoking dependence. The current study extends this work to determine if flavor, without nicotine, is a 
central feature of the development of smoking dependence.  
A 0.4 mg cigarette will be used in the current study to maximize efficacy for reducing smoking 
dependence and rates of compliance and retention, while minimizing the chance of compensatory 
smoking. In a large clinical trial, reduced nicotine content (RNC) cigarettes of 0.4 mg were associated 
with the largest reductions in the number of cigarettes smoked per day, urinary nicotine, and subjective 
ratings of withdrawal and dependence compared to all other nicotine contents.35 A separate study 
found that cigarettes at 0.3 mg increased compensatory smoking over 0.5 mg cigarettes.41 Preliminary 
results from the Penn State RNC trial with low socioeconomic status (SES) smokers shows that ratings of 
cigarette satisfaction only dropped 38% over the 7-month trial despite the 97% reductions in nicotine 
content, which likely contributes to their high rates of compliance and retention. In addition, preliminary 
fMRI research has shown that RNC cigarettes (2.4 mg) paired with a 21 mg nicotine patch was related to 
reductions in BOLD activation to smoking-related cues and increased activation to neutral cues in the 
amygdala after only 2 weeks.34 Reduced activation in the thalamus over the course of intervention was 
predictive of improved cessation outcomes in a post-treatment quit attempt.34 
 
2.3 
Study Rationale 
Tobacco use is the leading cause of preventable death in the U.S.3 Smoking dependence is in part 
maintained by three interrelated cognitive processes; 1) enhanced incentive salience of smoking 
stimuli42,43, 2) diminished incentive salience of non-smoking rewards,14,44,45 and 3) impairments in 
executive control25. These interrelated processes lead to poorly controlled motivational drives to smoke 
and contribute to smoking maintenance and relapse during quit attempts.46,47  
The incentive salience, or motivational value, of conditioned smoking stimuli becomes enhanced for 
regular smokers.48 This is evident in the subjective and physiological reactivity smokers show in response 
to smoking-related cues.49 In the laboratory, visual, tactile, and auditory smoking stimuli can elicit strong 
cigarette craving, shorter latency to smoking, and more frequent, higher volume cigarette puffs.50 
Flavor, a combination of odor and taste, is one smoking stimuli that has interested tobacco companies 
for its potential to increase dependence on cigarettes.51,52 Despite evidence supporting the role of flavor 
in addiction and the rising popularity of new flavored tobacco products, we currently know little about 
the neurobiological impact of flavor on the development and maintenance of smoking dependence. This 

Page 6 of 31 (V.04/27/2017) 
is a research priority for NIH’s Tobacco Regulatory Science Research Program due to its potential to 
inform tobacco policy.53 
Alternatively, the salience of non-smoking incentives, such as money, food, and socioemotional stimuli, 
is diminished among smokers.12 This is evident by smokers’ attenuated neural reactivity to the 
anticipation and receipt of monetary and food rewards during laboratory tasks compared to non-
smokers.13-15 Attenuation of reward reactivity, most notable in the striatum during states of acute 
smoking abstinence, has been associated with relapse during cessation attempts.14,15,54  
In addition to changes in incentive salience, there is growing evidence that smoking dependence is 
characterized by weakened executive control, in which “top-down” systems fail to inhibit the “bottom-
up” incentive salience processes that drive smoking motivation.17,55 Smokers show executive dysfunction 
in sustained attention, working memory, and inhibitory control processes during acute abstinence that 
are integral to maintaining goal-directed behavior during withdrawal.16-20 
We currently know little about how neural activity and connectivity of the incentive salience and 
executive control circuitry change during recovery. Given the advancements in pharmacotherapy and 
non-invasive brain stimulation techniques,30,31 gaining a nuanced understanding of how brain circuitry 
adapts during rehabilitation could identify neural targets for treatment. VLNC cigarettes have been used 
as an extinction-based cessation treatment to reduce the rewarding effects of cigarettes by significantly 
reducing nicotine delivery during smoking.6,34 Over the course of a VLNC extinction trial with nicotine 
replacement therapy, smokers’ reactivity in the amygdala to smoking over neutral visual cues 
decreased.34 Participants who successfully abstained in a quit attempt following the extinction trial had 
reduced cue reactivity in the thalamus and ventral striatum compared to participants who relapsed.34 
The central hypothesis underlying this award is that brain circuitry associated with incentive salience 
valuation and executive control can be altered by treatment interventions and, consequently, serve as 
potential neuromarkers of dependence reduction and cessation treatment outcomes. In a double-blind, 
randomized controlled trial, dependent smokers will be randomized to a 6-week VLNC cigarette 
intervention (N=50) or a 6-week normal nicotine content cigarette control condition (NNC; N=25). 
Participants will undergo fMRI scans at baseline, and 6-weeks to investigate the treatment-related 
modulation of brain circuitry involved in incentive salience valuation and executive control. Imaging 
tasks will assess the incentive salience of smoking cues and non-smoking rewards and executive function 
to identify changes in functional activity within, and effective connectivity between, known salience and 
executive control brain circuitry. A novel fMRI task using specialized odor presentation equipment and 
fMRI sequences will assess neural cue reactivity to smoke odors. 
 
3.0 
Inclusion and Exclusion Criteria 
 
3.1 
Inclusion Criteria 
1. 21-60 years old  
2. Smoke ≥5 cigarettes per day 
3. >1 year of daily smoking  
4. No quit attempt in prior month and not planning to quit smoking within next 3 months  
5. Able to understand and consent to study procedures 
6. Educational attainment < college degree or annual household income < $50,000 
7. Plan to live in local area next 3 months 
8. Women not pregnant or nursing and not planning to become pregnant in the next 3 months 
9. Able to read and write in English 
10. Access to computer with internet service that allows for Zoom 
 
3.2 
Exclusion Criteria 
1. Use of non-cigarette tobacco products in the past 7 days 
2. Use of illicit substances more than once a week in the past 3 months (excluding marijuana) 
3. Current alcohol abuse impairing participation 

Page 7 of 31 (V.04/27/2017) 
4. MRI safety contraindications (e.g., metal implants, claustrophobia) 
5. Unstable or significant medical conditions (e.g., COPD, coronary heart disease) 
6. Major neurological conditions or brain trauma 
7. Major surgeries planned in next 3 months 
8. Use of smoking cessation medication in prior month (e.g., varenicline, patch) 
9. Uncontrolled serious mental illness, suicidality, or inpatient psychiatric hospitalization in the past 6 
months  
10. Unwillingness to provide urine samples 
11. Unwilling to smoke study assigned cigarettes for the remainder of the trial  
12. Plans to move or take extended travel out of the area in the next 3 months 
13. Any other condition or situation that would, in the investigator’s opinion, make it unlikely that the 
participant could comply with the study protocol 
14. Self-reported color blindness 
15. Left-handedness 
16. Smell dysfunction as determined via standardized assessment 
 
3.3 
Early Withdrawal of Subjects 
 
3.3.1 
Criteria for removal from study 
▪ 
Excessive visit cancellations or no-shows. 
▪ 
Inability to attend the study visit within the allowed visit window. 
▪ 
Inability or unwillingness to smoke study cigarettes. 
▪ 
Lost contact. 
▪ 
Pregnancy (confirmed by urinary pregnancy test at each MRI visit).  
▪ 
Suicide attempts 
▪ 
Cardiovascular (CVD) event: including MI (heart attack), PTCA (angioplasty/stenting), bypass 
surgery, stroke, peripheral vascular disease, arrhythmias and new valvular disease (e.g., mitral 
or aortic regurgitation). 
▪ 
DVT/PE (deep vein thrombosis/pulmonary embolism) 
▪ 
Participants may choose to remove themselves from the study by informing the research team 
at any point during the study. 
▪ 
Significant baseline smoking rate increase at 3-week check-in or post-scan visit. Either one, or 
both criteria combined: 
• 
The average CPD increases by more than 100% from the average CPD on the baseline 
cigarette log. 
▪ 
Worsening substance use in which the participant is behaving inappropriately at visits or 
demonstrates an inability to continue with the study. 
▪ 
Any hospitalization in which participation in the study could be detrimental to the recovery 
process. (e.g., recovery from a major surgery, etc.) 
▪ 
Any situation where participant is not able to smoke research cigarettes for a period of more 
than 3 days 
▪ 
Participant doesn’t comply with the protocol, behaves in an inappropriate or threatening 
manner, admits to lying about eligibility criteria, or is participating in other smoking research 
studies that could affect the primary outcome measures. 
 
 
3.3.2 
Follow-up for withdrawn subjects 
Participants who report an inability to smoke research study cigarettes will be asked to 
complete a final MRI scan visit before being withdrawn from the study. 
 
4.0 
Recruitment Methods 
 

Page 8 of 31 (V.04/27/2017) 
4.1 
Identification of subjects 
All recruitment for this study will be routed through IRB Protocol #2213 which will also serve as the 
initial recruitment point of contact. 
 
4.2 
Recruitment process 
Interested volunteers will complete a brief phone screen to determine preliminary eligibility and to learn 
more about the study. Interested and eligible participants will be scheduled for an in-person screening 
visit. Subjects that were unable to be contacted via phone will be sent an email asking them to reach out 
to the study team if they are interested. 
 
4.3 
Recruitment materials 
The study will be described to interested volunteers over the phone using the phone screening script.  
 
4.4 
Eligibility/screening of subjects 
 
Study staff will collect preliminary eligibility information over the phone. A full script and screening 
questions for this study are in the “Consent Forms and Recruitment Materials” section of the IRB 
application. 
 
 
After a participant has met preliminary eligibility criteria over the phone, they will be scheduled to 
complete a final screening over the phone or ZOOM  to determine study eligibility. See “7.0 Study 
Design and Procedures” and “Supporting Documents” for details on the screening assessment tools. 
 
5.0 
Consent Process and Documentation 
 
5.1 
Consent Process  
  
5.1.1 
Obtaining Informed Consent 
 
5.1.1.1 
Timing and Location of Consent 
Screening portion: Subjects will have the screening portion of the study 
explained to them in detail over a phone call. They will have the opportunity to 
ask any questions and then will be asked to give their verbal consent to take 
part in the screening portion. 
 
Randomization/MRI portion: During the phone screen, participants will have the 
study explained to them in detail, and be mailed a long form consent form to 
look over before their first MRI visit. They will have the opportunity to ask 
questions at both visits and then will be asked to sign their consent form at the 
MRI visit.  
 
5.1.1.2 
Coercion or Undue Influence during Consent 
Once potential study volunteers are identified they will be given information 
about the study and offered the opportunity to participate. The researchers 
obtaining consent will be instructed to clearly indicate that the participant’s 
enrolling in the trial is purely voluntary and the researchers will not offer 
comments about whether they believe the participant should enroll in the study 
or not. Given the number of contacts and visits involved in the study protocol, 
the compensation provided to the participant is modest. 
 
5.1.2 
Waiver or alteration of the informed consent requirement 
N/A 

Page 9 of 31 (V.04/27/2017) 
 
5.2 
Consent Documentation 
 
5.2.1 
Written Documentation of Consent 
 
The consent process will be documented in writing as follows:: 
• 
The current IRB approved long form written consent form will be used. 
• 
The subject will sign the consent form during their MRI visit after both screenings have 
taken place.  
• 
• 
A copy of the consent form will be provided to the subject/representative. 
Whenever possible the consent form will be provided to the subject in advance of the 
consent discussion. 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
Volunteers who are interested in the study will be asked to provide verbal consent to allow the 
researcher to screen them for the study during a phone and a remote screening contact. First, 
volunteers will provide informed verbal consent prior to completing a brief phone screen to 
determine preliminary eligibility. Second, volunteers who meet preliminary eligibility, will 
complete a more in-depth screening assessment via ZOOM to determine final study eligibility. 
Volunteers will be emailed an electronic copy and mailed a paper copy of the Summary 
Explanation of Research prior to the final phone screen. Participants will be asked if their 
screening information can be retained so that the study team will know reasons that 
participants are not eligible for the study. The screening takes place prior to the randomization 
portion of the study and involves low risk procedures.   
 
In addition, participants who are not eligible for the study, or those who begin the screening 
procedures but are not interested in completing it after learning more about the study, will be 
asked if they would be interested in being contacted for future studies being conducted by our 
research team. They will be informed that by providing their name and phone number, they will 
be consenting to allow the study team to contact them in the future. 
 
 
5.3 
Consent – Other Considerations  
N/A 
5.3.1 
Non-English Speaking Subjects 
 
5.3.2 
Cognitively Impaired Adults 
 
5.3.2.1 Capability of Providing Consent 
 
5.3.2.2 
Adults Unable To Consent 
 
5.3.2.3 Assent of Adults Unable to Consent 
 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
 
5.3.3.1 Parental Permission 
 
5.3.3.2 Assent of subjects who are not yet adults 
 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
 

Page 10 of 31 (V.04/27/2017) 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
  
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
6.2.1 
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual 
 
6.2.1.1 Plan to protect PHI from improper use or disclosure 
 
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol. 
 
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers  
 
All identifiers stored electronically will be permanently deleted, including the keys 
linking participant ID numbers to their identifying information and paper consent 
forms will be shredded before disposal according to federal regulations and 
institutional policies.  
 
6.2.2 
Explanation for why the research could not practicably be conducted without access to and 
use of PHI 
 
Information must be obtained from the subject during recruitment to determine/confirm 
eligibility.  The screening visits will collect PHI to confirm eligibility (date of birth) and to allow 
for scheduling/reminders of future visits which requires us to have complete contact 
information.  
 
6.2.3 
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization 
 
Determining/Confirming eligibility prior to obtaining consent will ensure only eligible subjects 
are enrolled in the study. Several factors make the collection of written informed consent prior 
to the randomization visit impractical, including; time constraints with the use of the MRI 
facility,the requirement that subjects record their daily cigarette usage between screening 
determination and the randomization visit, the need to prepare product for dispensation 

Page 11 of 31 (V.04/27/2017) 
between eligibility determination and the randomization visit, and the risk of unnecessary 
burden on volunteers. 
 
6.3 
Waiver or alteration of authorization statements of agreement 
 
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations.  
 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations.  
 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented. 
 
7.0 
Study Design and Procedures 
 
7.1 
Study Design 
 
This is a two-arm, randomized, double-blind parallel group trial. Smokers will be randomly assigned to 
smoke very low nicotine content (VLNC) (n=50) or normal nicotine content (NNC) (n=25) SPECTRUM 
cigarettes for 6 weeks. Participants and study staff will be blind to the experimental cigarette allocation 
until the study is complete. The groups will be stratified by gender.  
 
7.2 
Study Procedures 
 
7.2.1 
Final remote screen (Week 0)  
A Penn State Health Zoom meeting link will be emailed to participant for the previously 
scheduled time.  
 
A standardized smell test (this standardized test includes a No. 2 pencil and a pamphlet that the 
participant will complete on the Zoom meeting to allow the study team member to oversee the 
completion; the test will be scored over the Zoom session), paper cigarette logs, folder, written 
consent form, summary explanation of research, welcome letter and visit reminder card will be 
mailed to the participant to arrive before scheduled Zoom meeting. If there is a delay in the 
mail, the Zoom screening visit will be rescheduled. 
 
The following information will be collected to determine eligibility and collect baseline 
information: 
1. 
REDCap Survey Questionnaires: 
1. Compliance questionnaire  
2. Tobacco use history 
3. Demographics 
4. Legal history 
5. Audit C 
6. Butt-out  
7. Environmental Smoke Questionnaire 
8. Social support 
9. Smoking Motivation (WISDM-Brief) 
10. Craving questionnaire 
2. 
Interview 

Page 12 of 31 (V.04/27/2017) 
1. Visit screener 
2. Medical history and medications 
3. NIDA Substance use quick screen 
4. Cigarette details 
5. Concomitant medications 
3. 
Biomarkers  
1. Smell function will be assessed with the B-SIT Test. Gender-normed standard scores 
will be used to determine if participants have normal smell function for eligibility.  
4. 
Participants will complete computerized decision-making tasks to gain familiarity prior 
to the MRI scan. The tasks include a stroop interference task, monetary temporal 
discounting task, and a Smoking Go/NoGo task. Participants will be shown a powerpoint 
that explains the screens/images they will see while in the MRI during an odor-cue 
reactivity task All tasks will be completed in approximately 15 minutes.  
5. 
At the end of the visit, participants will be asked to keep a log of the cigarettes they 
smoke each day until their next visit. Participants will receive a daily REDCap survey link 
via text message using the Twilio service. The survey will ask participants to record the 
frequency and type of tobacco and alcohol used that day. Participants will be instructed 
on how to complete the survey and will be provided with a paper log to tally their 
cigarette use throughout the day. Participants who are unable or unwilling to receive 
study text messages will track their cigarette use on the paper log only. The REDCap or 
paper daily cigarette log surveys are not mandatory for participation.  
 
Time commitment: 1.5 hour 
 
Participants will be asked to refrain from smoking for 14 hours prior to MRI Visit 1. A Zoom call 
(Remote Visit 1) and In-person visit (MRI Visit 1) will be scheduled.  
 
7.2.2 
MRI visit 1 
 
Participants will complete the following procedures in person after refraining from smoking for 
14 hours prior to the visit. 
 
Participants will sign their long form written consent at this visit prior to any further study 
procedures.  
 
1. REDCap Survey Questionnaire 
a. Nicotine Withdrawal (MNWS)  
b. Smoking Urges (QSU)  
c. Craving questionnaire 
2. Interview 
a.     Penn State CNMRR MRI Safety 
b.     Scent Ratings post MRI Scan 
 
3. Biomarkers  
a. Urine collection for cotinine analysis and pregnancy determination: Obtain urine and 
process pregnancy test for women of child bearing age (have had a period in the past 
12 months) who have not had a hysterectomy. 
b. Saliva collection for potential cotinine analysis, micro RNA (miRNA) biomarker analysis 
and use in future research. 
c. Exhaled carbon monoxide will be measured using a hand-held monitor.  
 

Page 13 of 31 (V.04/27/2017) 
4. A member of the study team will first review the MRI safety sheet and determine that it is 
safe for the participant to be scanned. If safe, participants will complete a one-hour MRI 
scan that will include the following tasks. 
 
The risks and discomforts associated with this project are the same as that associated with 
standard clinical MRI and EEG studies, which are minimal. Risk exists from radio frequency 
heating of the head, but is safe at the specific absorption rate (SAR) limits prescribed by the 
FDA. The SAR of radiofrequency field exposure is monitored throughout the study and 
maintained below the limits established by the FDA. 
 
The second risk is the potential danger of the magnetic field, which can produce injury if 
ferromagnetic devices are accidentally brought into proximity of the magnet. All patients and 
staff are screened for magnetic objects, and access to the magnet area is restricted. Discomforts 
may be caused by claustrophobic environment in the MRI scanner to some subjects as well as 
from the loud tapping noises made during the scan process. 
 
a. 
High resolution anatomical scan (~10 minutes) 
b. 
Monetary temporal discounting task (~15 mins).  
Participants will be asked to choose 96 times via button box between two options with 
specified dollar amounts and time delays to receipt of the money.  
 
c. 
Tobacco odor cue-reactivity task (~15 minutes) 
An odor cue-reactivity task will be used to compare neural reactivity to tobacco, 
strawberry vanilla, and neutral odors. Two runs of alternating blocks of tobacco smoke 
odor, strawberry vanilla odor, and neutral odor (propylene glycol) will be delivered for 
15 presentations. The odor will be presented for 6 seconds followed by 22 to 38 seconds 
of no odor (fresh air). A standardized MRI-compatible olfactometer at the Penn State 
CNMRR will be used to deliver odors inside the scanner at the opening of the 
participant’s nose through plastic Teflon tubing. Participants will wear a respiration belt 
that will monitor the natural pace of their breathing to deliver the odor prior to 
inhalation. The odors will be presented in randomized order.  

Page 14 of 31 (V.04/27/2017) 
 
 
d. 
Smoking Go/NoGo task (~25 mins) 
Using a button box inside the scanner, participants will press a button (Go) as quickly as 
possible or inhibit their button press (NoGo) when presented with smoking and non-
smoking  pictures bordered in blue or yellow. Participants will respond to 768 pictures 
total in pseudorandomized order.  
 
 
 
5. Prior to the visit, an unblinded member of the study team will randomize the participant to 
either the VLNC or NNC cigarette group based on a pre-determined block randomization list. 
The unblinded study member will identify the cigarette packs with the assigned nicotine 
content by NRC code and prepare them for redistribution by re-labeling each pack with the 
participant ID number and a label indicating these are research cigarettes   The unblinded 
study member will keep records of the RTI log numbers of the packs dispensed to each 
participant at each visit.   At the end of MRI Visit 1 participants will be given an ample 6-
week supply of their assigned cigarette (125% of baseline cigarettes per day) and instructed 
to only smoke study cigarettes until their next scheduled appointment. Participants may 
contact the study team to receive more study cigarettes if they run out prior to their next 
visit unless this is more than a 100% increase from their baseline CPD. Participants will be 
instructed to continue completing the daily REDCap cigarette log surveys that they receive 
via text message and will also be given paper cigarette logs to track use throughout the day.  
 
Time commitment: 2 hours 

Page 15 of 31 (V.04/27/2017) 
 
7.2.3 
Remote visit 1 (scheduled for +1 to +3 day(s) of in person MRI visit)  
Participants will complete the following procedures over Zoom  
1. REDCap Survey Questionnaire 
a. 
Depression (CESD) 
b. 
COPD (CCQ) 
c. 
Psychological Distress (Kessler K6) 
d. 
Nicotine Dependence  
e. 
Anxiety (ASQ) 
f. 
Sleep Disturbance 
g. 
Cigarette Liking 
h. 
Stages of Change 
i. 
Perceived Stress  
2. Interview 
a. 
Concomitant medications 
b. 
Adverse event trigger questions 
3. Out of scanner tasks 
a. 
Participants will complete a monetary temporal discounting task. During this 
computerized task, participants will choose between two options with specified 
dollar amounts and time delays to receipt of money (see MRI task image below).  
b. 
Participants will complete a computerized stroop interference task where they 
will view color words printed in the same color (i.e., blue, red, yellow, green), 
color words printed in an incongruent color (e.g., “blue” printed in red), and 
color neutral words printed in color (e.g., “hat” printed in red). Participants will 
be asked choose what color each word is printed in by pressing a button labeled 
to indicate each color.   
 
 
 
 
7.2.4 
Phone call 1 
Participants will be contacted in the 2nd week of the randomization phase to check-in regarding 
their next scheduled appointment and their success with cigarette tracking and study cigarette 
compliance. 
 
Time commitment: 15 minutes 
 
7.2.5 
Remote visit 2 (Week 3 ± 5 days)  
Participants will complete a Zoom call three weeks into the randomization phase. During this 
visit participants will complete the following activities: 
1. 
Review cigarette tracking logs with study staff.   
2. 
Concomitant medication 
3. 
Adverse event trigger questions 
4. 
Discuss and problem-solve barriers to adherence 
5. 
Computerized REDCap Survey Questionnaires (see Remote Visit 1 and MRI Visit 1) 
6.  
Complete computerized out-of-scanner tasks.  
 
Time commitment: 1 hours 
 
Participants will be asked to refrain from smoking for 14 hours prior to MRI visit 2. The MRI visit 
2 and Remote visit 3 will be scheduled. 
 

Page 16 of 31 (V.04/27/2017) 
7.2.6 
Phone call 2 
Participants will be contacted in the 4th week of the randomization phase to check-in regarding 
their next scheduled appointment and their success with cigarette tracking and study cigarette 
compliance. 
 
Time commitment: 15 minutes 
 
7.2.7 
Remote visit 3 (scheduled for -1 to +1 day of in person MRI visit)  
Participants will complete the following procedures over a Zoom call 
 
1. Concomitant medications 
2. Adverse event trigger questions  
3. Perceived health risk rating 
4. Computerized REDCap Survey Questionnaires (see Remote Visit 1) 
5. Review cigarette tracking logs.  
6. Complete computerized out-of-scanner tasks 
7. Complete quit choice survey and counseling. Participants will be reminded that they will receive 
a text message survey in 12 weeks asking for information on quit attempts.   
 
7.2.8 MRI visit 2 (Week 6 ± 5 days)  
 
Participants will return to the CNMRR Center for their final MRI scan after refraining from smoking for 
14 hours prior to the visit. 
 
For the final study visit, participants will complete the following activities:  
1. Return all (empty and full) cigarettes packs  
2. Penn State CNMRR MRI safety and Scent Ratings (post MRI) 
3. Urine collection for cotinine analysis and pregnancy determination: Obtain urine and process 
pregnancy test for women of child bearing age (have had a period in the past 12 months) who 
have not had a hysterectomy 
4. Saliva collection for potential cotinine analysis, micro RNA (miRNA) biomarker analysis, and use 
in future research.  
5. Exhaled carbon monoxide will be measured using a hand-held monitor.  
6. Computerized REDCap Survey Questionnaires (nicotine withdrawal, smoking urges, craving) 
7. The MRI technologist will first review the MRI safety sheet and determine that it is safe for the 
participant to be scanned. If safe, participants will complete a one-hour MRI scan.  
 
Time commitment: 2 hours 
 
7.2.7 
Text message with quit attempt survey (Week 18 ± 5 days) 
 
Participants will receive a text message with a REDCap survey link inquiring about current smoking 
status and past 12-week quit attempts. Participants will be sent a second text message if they do not 
complete the survey within 72 hours of the first message. The study coordinator will call participants 
who are unwilling or unable to receive text messages to complete the survey. 
 
7.3 
Duration of Participation 
Participants who complete all study visits in the ideal time frame will be in the study for 18 weeks. The 
majority of participants are expected to complete the study in 7 to 18 weeks. 
 

Page 17 of 31 (V.04/27/2017) 
7.4 
Test Article(s) (Study Drug(s) and/or Study Device(s)) 
 
7.4.1 Description 
Participants will be provided with research cigarettes that have a similar nicotine content to 
current commercially available cigarettes (11.6mg) or a very low nicotine content (0.29mg). 
Participants will have a 0.67 probability of being assigned to the very low nicotine content 
research cigarette and a 0.33 probability of being assigned to the usual nicotine content 
cigarette. The cigarettes will be managed by an unblinded study member. 
 
7.4.2 Treatment Regimen 
Participant will be asked to smoke their assigned study research cigarettes (11.6 mg or 0.29 mg 
nicotine content) for 6 weeks.  
 
7.4.3 Method for Assigning Subject to Treatment Groups 
Participants will be randomized to one of two experimental conditions based on a blocked 
randomization sequence stratified by gender. A 2:1 randomization strategy will be used, 
resulting in 0.67 probability of being assigned to the very low nicotine cigarette, and a 0.33 
probability of being assigned to the usual nicotine cigarette.  The randomization key will be 
stored in REDCap and will be accessible only to unblinded study members and the faculty 
project mentor. The principal investigator will not have access to the code to ensure blinding.  
 
7.4.4 Subject Compliance Monitoring 
Participants will track the number of cigarettes they smoke each day in the REDCap surveys sent 
to them via text message and using a paper tally tracking log. Participants will be given detailed 
instructions on how to complete the logs and they will be reminded at each study contact to 
only use the research cigarettes they have been given. Questions will be asked at each contact 
to review their log and verify how many cigarettes they are smoking each day. Participants will 
also be asked to self-report their other tobacco use including products such as cigars, pipes, 
chew, snus, dip, hookah, electronic cigarettes and dissolvable tobacco. Exhaled carbon 
monoxide measurements, urine, and saliva will be taken at each contact to verify smoking 
intensity and cotinine levels. 
 
7.4.5 Blinding of the Test Article 
Cigarette cartons will arrive to the PI’s laboratory with a packaging slip that provides 
information about the cartons in the shipment which includes the NRC code nicotine content, 
RTI log carton bar code number and a batch/lot number. Each carton is labeled with the RTI Log 
number.  The RTI Log number and corresponding NRC code will be carefully recorded by the  
unblinded study member in the REDCap randomization database. Individual packs do not 
contain any identifiable information; however with each shipment a set of labels indicating the 
RTI log numbers are also included.  At the time of dispensing, the unblinded study team member 
will remove the RTI log number from the carton.  If less than a full carton is dispensed to a 
participant, the remaining packs in the carton will be labeled with the RTI log number labels.  At 
the time each pack is dispensed, the RTI log number label will be removed and maintained by 
the unblinded study team member as confirmation that the correct product was dispensed to 
the subject at the visit.   
 
7.4.6 
Receiving, Storage, Dispensing and Return  
 
7.4.6.1 
Receipt of Test Article  
Experimental cigarettes will be provided free of charge to the investigators via 
the NIDA Drug Supply Program (see Notice: NOT-DA-13-002). Cartons (10 
packs/carton) with packs of 20 cigarettes/pack will be received from the 
Research Triangle Institute in North Carolina. 

Page 18 of 31 (V.04/27/2017) 
 
7.4.6.2 
Storage 
At Penn State Hershey, cigarettes will be stored in locked, -20 freezers that are 
maintained by the PI’s Department. Standard laboratory protocols for freezer 
temperature control monitoring and recording will be followed. Prior to 
cigarette assignment, the cigarettes may be stored unfrozen for a period of time 
up to 3 weeks. 
 
7.4.6.3 
Preparation and Dispensing 
Assignment: When a new participant is randomized, they will receive the packs 
labeled with their study ID number indicating that these are research cigarettes.   
 
Preparation: Once the cigarettes are received, they will be blinded by the 
unblinded study member. At the time of dispensation, the unblinded study 
member will prepare a bag of cigarette packs labeled with the participant ID 
number and indicating that they are research cigarettes.  The RTI log number 
labels will be removed from the packs/cartons at the time of preparation for 
dispensing. 
 
Where: All receiving, sorting, blinding of the initial study product will be done by 
an unblinded member of the study team in a designated space for this study at 
Penn State Hershey. Dispensing of product to study participants will occur at the 
Center for NMR Research where participants will complete their MRI visits.  
 
Dispensing: Cigarette packs containing 20 cigarettes will be prepared by the 
unblinded study member prior to a participant’s in person visit. All packs will be 
given to participants in the original packaging. Each individual pack of cigarettes 
will have a label with the participant ID number and a list of possible nicotine 
doses the cigarettes may contain. The coordinator will give the cigarettes to the 
participant at their second visit. The number of packs dispensed will be 
determined by the self-reported number of cigarettes per day they smoke 
determined by the baseline week cigarette log. Participants will be provided 
with 125% of the cigarettes necessary for each week of usual smoking. 
Participants will be able to smoke as many or as few cigarettes as they choose 
and will be required to return all packs (empty and full) at the next visit. 
 
7.4.6.4 
Return or Destruction of the Test Article 
The unblinded study member will track all receipt, dispensing, and blinding of 
cigarettes for the duration of the project. The study coordinator will track all 
dispensing of blinded cigarettes for the duration of the project. The unblinded 
study member will have access to receipt and dispensation logs to create 
reconciliation reports on an ongoing basis. Participants will be instructed to 
bring all research cigarette packs to the next visit, regardless of whether they 
are empty, unopened or partially used. The number of unused packs will be 
recorded and returned to the study participants at the end of the visit. We will 
not ship experimental cigarettes back to the NIDA Drug Supply Program.  Empty 
packs dispensed to and returned by study participants will be destroyed once 
the usage information has been documented. 
 
7.4.6.5 
 Prior and Concomitant Therapy 
Concomitant medication use will be collected regularly throughout the trial to 
serve as covariates during analysis and to monitor participant health conditions. 
Participants taking varenicline, bupropion or nortriptyline as a smoking 

Page 19 of 31 (V.04/27/2017) 
cessation medication in the prior month will be excluded from the study. 
Participants taking bupropion or nortriptyline for depression management and 
who expect to continue use of the medication throughout the trial will be 
eligible to participate. Additionally, participants who are prescribed bupropion 
or nortriptyline for depression management at any point during the study will 
be eligible to continue with the study. Medications related to certain medical 
conditions that are exclusions to the study, such as COPD and current heart 
conditions, will serve to alert the study staff of the presence of these conditions 
during screening. Once the participant is entered into the randomized double 
blind phase of the study, there are no medications that will interfere with the 
participant’s ability to participate. 
 
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
We expect to enroll approximately 90 participants in order to retain 75 study completers.  
 
8.2 
Sample size determination 
Dependent smokers of low SES (n=75) will be recruited for the current study through the TCORS study 
call center (protocol #2213). Two-thirds of the sample (n=50) will be randomized to the VLNC group to 
maximize power for the within-subjects repeated measures analyses while still allowing for an analysis 
of between-subjects effects. There is not currently an accepted method for determining sample size a 
priori for repeated measures fMRI designs. With repeated measures behavioral data, to detect a 
medium effect size (f=0.25) with 80% power and a Type I error rate of .05, a sample size of 28 is required 
to detect within-subjects effects, 86 for between-subject effects, and 28 for within x between 
interactions. The estimate for detecting such effects with fMRI is likely somewhat higher; however, my 
mentors have found within-subject effects with similar tasks that will be used for this project with 
comparable sample sizes; smoking cue reactivity (n=22)61 card-guessing task (n=44)5, and the n-back task 
(n=33)62. Thus, we estimate that the current design will have adequate power to detect small to medium 
within-subjects effects and medium to large between-subjects effects. The design will serve as pilot data 
to determine sample size for future studies. TCORS found retention rates of 85% for their 18-week trial 
and a prior 6-week VLNC intervention found retention rates at 92%.49 Retention for the proposed study 
will likely be higher given frequent contact with participants (3-week visit and two phone-check-ins); 
however, with a conservative estimate of 80% retention and adequate compliance, the final sample size 
(n=60) would still be adequately powered.  We will recruit until we have 75 study completers. It is likely 
that participants that complete informed consent at the remote screening will be ineligible. Therefore, 
we expect around 90 participants to complete informed consent and 75 to complete the entire study. 
 
8.3 
Statistical methods 
Data Analysis. Images will be preprocessed using FSL, including registration to high resolution 
anatomical images and standard space, brain extraction, slice timing correction, spatial and temporal 
smoothing, intensity normalization, physiological noise correction, and motion correction for 6 motion 
parameters and artifacts identified via ICA-AROMA.63 For task-based images, contrasts of the relevant 
conditions will be determined during first level analyses as described above and averaged across 
multiple runs for each participant.  
 
Aim 1: Examine the longitudinal effect of VLNC cigarettes on changes in task-related functional neural 
activation within brain circuitry associated with incentive salience valuation and executive function. 
Treatment-related within-subject and between-subject changes in BOLD activation during all fMRI tasks 
will be assessed in linear mixed-effects models using FSL software. Whole-brain analyses and ROI 
analyses based on pre-determined salience and executive control circuitry will be conducted. Paired t-
tests will identify anatomical regions showing statistically significant differences from baseline to 6-week 
scans across groups.   

Page 20 of 31 (V.04/27/2017) 
 
Aim 2: Assess the longitudinal effect of VLNC cigarettes on changes in effective (directional) 
connectivity between incentive salience and executive control brain circuitry. Dynamic causal 
modeling (DCM) using SPM12 software will measure effective connectivity between ROIs in the 
incentive salience and executive control networks.64 Specifically, DCM identifies models with task-
specific increases in the dependence of the BOLD activity timecourses between a priori selected nodes 
and estimates directionality. We expect that the use of the VLNC cigarettes will strengthen the influence 
of the executive control over incentive salience circuitry during the smoking Go/NoGo and temporal 
discounting tasks. ROIs will be selected a priori for these analyses. Given the novelty of the odor cue 
reactivity task, active brain circuitry identified in Aim 1 will be included as nodes in the DCM model to 
test the hypothesis that non-smoking reward circuitry will exert an increasing influence over smoking 
salience circuitry. Connectivity estimates from the models will be included in a mixed-effects ANOVA to 
determine between-subjects and within-subject effects across the trial.  
 
Aim 3: Establish measurable and objective neural outcomes of successful reductions in smoking 
dependence. FSL’s Randomise one-sample t-test will be conducted on change scores to determine if 
changes in BOLD activity are associated with reductions in subjective markers of dependence (FTND, 
HONC, MNWS, QSU), cigarettes smoked per day, and quit intention and success. Changes in connectivity 
estimates will be correlated with changes in subjective and behavioral outcomes. 
9.0 
Confidentiality, Privacy and Data Management  
 
9.1 
Confidentiality 
See the Research Data Plan Review Form 
 
9.1.1 
Identifiers associated with data and/or specimens 
 
 
9.1.1.1 Use of Codes, Master List 
 
9.1.2 
Storage of Data and/or Specimens 
 
9.1.3 
Access to Data and/or Specimens 
 
9.1.4 
Transferring Data and/or Specimens 
 
9.2 
Subject Privacy 
 
10.0 Data and Safety Monitoring Plan 
 
10.1 
Periodic evaluation of data 
The study coordinator will be responsible for the daily oversight of subject safety. Research staff will 
assess for adverse events at each study visit and will make appropriate referrals to medical providers. 
Dr. Hobkirk, will meet regularly with the study staff to review participant’s progress and their 
experiences with the tobacco products, including any adverse events. Entrance criteria will be reviewed 
following screening. Medical history will be reviewed by Dr. Hobkirk for any contraindications for the 
treatment products and smoking behavior will be checked at each visit.  
 
10.2 
Data that are reviewed 
Data that will be reviewed include: 
• 
Accrual and retention 
• 
Adverse events and serious adverse events 
• 
Protocol deviations/violations 
• 
Misconduct 

Page 21 of 31 (V.04/27/2017) 
• 
Conflict of interest 
• 
Participants’ ability to achieve study requirements 
• 
Changes in cigarette consumption from baseline 
 
10.3 
Method of collection of safety information 
All data, including safety data, will be coded directly into REDCap case report forms during study visits, 
over the phone or via online REDCap survey. Participant adverse events and serious adverse events will 
be assessed at each in-person study visit but can be reported at any time during the study. 
 
10.4 
Frequency of data collection 
Safety data including adverse events and serious adverse events will be collected at each in-person visit. 
Cigarettes smoked per day will be collected regularly at in person visits. 
 
10.5 
Individuals reviewing the data 
The study coordinator will be responsible for the daily oversight of subject safety. Dr. Hobkirk, will meet 
regularly with the study staff to review participants’ progress and their experiences with the tobacco 
products, including any adverse events. 
 
10.6 
Frequency of review of cumulative data 
Safety data will be reviewed cumulatively every six months by the principal investigator. 
 
10.7 
Statistical tests 
Statistical methods will be used to analyze the safety data to determine whether harms are occurring. 
Paired sample t-test (or nonparametric Wilcoxon Rank-Sum test) will be used to examine the changes in 
cigarette consumption from the baseline. In addition, the point estimates and 95% confidence intervals 
for the accrual and retention-dropout rate, completion rate, and the proportions of adverse events and 
serious adverse events will be generated. The data will not be reviewed across treatment groups to 
maintain blinding; however, if the principal investigator perceives a need to assess safety based on an 
unblinded analysis, she can request this information and it will be provided. 
 
10.8 
Suspension of research 
Due to the low risk of the intervention, it is unlikely that there will be a need to suspend the research. 
However, should the principal investigator identify any issues after reviewing the data, stopping rules for 
the trial will be developed and followed. 
 
11.0 Risks 
Potential risks for subjects are minimal. The cigarettes which will be administered to subjects have been 
previously tested and found to be of no greater risk than cigarettes the participants are already using. Only 
regular smokers who are not planning to quit will be recruited to the study. All participants will be free to reduce 
or quit smoking throughout the study, and smoking cessation counseling will be given to all participants at the 
end of the study. Subjects will be under supervision throughout their participation in the study and adverse 
symptoms will be recorded at each visit and monitored by the Principal investigator. The major side effects 
associated with RNC cigarettes are similar to usual brand cigarettes.  
 
Additional potential risks include: 
 
• 
Magnetic resonance imaging: MRI does not involve radiation and there are no known long-term risks of 
MRI. Participants will be assessed for MRI safety at the screening visit and again at each scan visit before 
entering the scanner. We will be assessing for potential MRI hazards like metal fragments in the body or metal 
implanted devices that could shift during scanning. Participants will be instructed to remove all metal from their 
body and clothing before entering the scanning room. The major discomforts of fMRI scanning include lying still 
in a supine position for a sustained period of time and hearing loud tapping sounds during image acquisition. 
 Participants may be uncomfortable inside the MRI scanner, especially if they do not like to be in closed spaces 

Page 22 of 31 (V.04/27/2017) 
(“claustrophobia”). In between tasks, participants will be able to talk with the MRI staff through a speaker 
system. At any time, the participant can choose to stop the scan by squeezing a button. 
• 
The scans done during this study are NOT designed to detect or evaluate any medical condition. They 
are intended solely for research purposes. The investigators for this project are not trained to perform medical 
diagnosis, and the scans to be performed in the study are not optimized to find abnormalities. On occasion, a 
member of the research team may notice a finding on a scan that seems abnormal. When a finding is noticed, 
one of the investigators may consult a physician specialist, such as a radiologist or neurologist, as to whether the 
finding merits further investigation. If the specialist recommends further follow-up, the investigator or another 
member of the research team will contact the participant within 48 hours of the recommendation and suggest 
that the participant contact his or her private medical provider for follow-up. To facilitate follow-up care, the 
participant may be given a copy of the images upon written request. Being told about a finding may cause the 
participant anxiety as well as suggest the need for additional tests and financial costs. Medical insurance may be 
affected whether or not the finding is ultimately proved to be of clinical significance. Costs for clinical follow-up 
will not be covered in the cost of research. Participants will be told that their decision as to whether to proceed 
with further examination or treatment is their own. 
• 
Increased compensatory smoking: Compensatory smoking may lead to increased levels of toxicant exposure. 
In prior studies, compensatory smoking was minimal and higher levels of toxicant exposure were generally not 
observed. Cigarette consumption will be monitored throughout the 6-week randomization phase. Safety rules 
are in place to identify and remove participants who increase their smoking rate significantly. 
• 
Nicotine withdrawal symptoms: Decreased nicotine cigarettes and abstaining from nicotine may result 
in nicotine withdrawal symptoms (e.g. irritability, anxiety, restlessness, depressed mood, increased appetite, 
fatigue, insomnia/sleep problems, impatience, headache, difficulty concentrating, frustration, anger, craving for 
sweets, constipation, coughing, dizziness, nausea and sore throat). 
• 
New pregnancy or intention to become pregnant: Smoking is known to be harmful to the developing 
human fetus, either from cigarettes or at the recommended therapeutic dose of nicotine replacement therapy. 
Although there are no known risks of MRI during pregnancy to the woman or fetus, future unknown medical 
problems could occur. For these reasons women of child-bearing potential must not be trying to become 
pregnant during the study. Pregnancy status will be confirmed with a urinary pregnancy test at the screening 
visit and each scan visits. 
• 
Loss of confidentiality: There is a risk of loss of confidentiality if information is obtained by someone 
other than the investigators. Precautions will be taken to prevent this including direct coding of data in REDCap. 
• 
Randomization in clinical trials: Participants will be assigned to a treatment program by chance. The 
treatment they receive may prove to be less effective or to have more side effects than the other research 
treatment(s) or other available treatments. 
• 
Questionnaires: It is possible that some of the questions in the screening assessment interview or 
questionnaires may make participants uncomfortable. They will be instructed that they are free to skip any 
questions that make them uncomfortable. 
 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
There are minimal benefits to study participants other than the (uncertain) possibility that participation 
in the study may reduce their nicotine dependence. Those who complete the study will be offered 
smoking cessation counseling. 
 
12.2 
Potential Benefits to Others 
The main benefit to society and others from the study is a greater scientific understanding of the effect 
of switching to reduced nicotine content cigarettes on neuroadaptations in brain circuitry. This 
neurobiological process may be a target for future cessation treatment and can inform our basic 
understanding of addiction. 
 

Page 23 of 31 (V.04/27/2017) 
13.0 Sharing Results with Subjects 
This study is not designed to diagnose any disease or condition. However, if during the course of conducting 
clinical procedures (e.g., MRI), a participant is found to have a result outside of clinical norms, the result will be 
discussed with the participant at the visit where the result is identified (MRI) or via phone after the visit. The 
participant will be given a letter indicating what procedure was done and will direct them to contact a medical 
provider for further evaluation. If a woman tests positive for pregnancy, the results will be shared with the 
participant and they will be advised to follow up with their doctor for prenatal medical care. They will not be 
allowed to participate in the study. Abnormal medical results, adverse changes in mental health status, 
increased toxicant exposure (CO and cigarette consumption) and other outcomes of the study will be treated as 
Adverse Events. They will be discussed with the participant, documented and the results will be reviewed by the 
study PI. 
 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
All payments for time compensation, and study completion bonus will be added to their gift cards as they are 
earned. In total subject will earn up to $370 for participation in the study. 
 
Bonus description: Participants can receive a $75 bonus for returning used and unused cigarette packs, 
completing all cigarette logs and attending all study visits. 
 
Visit compensation:  
Final remote screen: $30 
MRI visit 1: $85  
Remote visit 1: No compensation 
Phone call 1: $15 
Remote visit 2: $65 
Phone call 2: $15 
Remote visit 3: No compensation 
MRI visit 2: $85 + $75 completion bonus 
12-week Follow-up Text Survey: No compensation 
 
 
15.0 Economic Burden to Subjects 
 
15.1 
Costs  
There are no costs that subjects will be responsible for related to the research. 
 
15.2 
Compensation for research-related injury 
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers. 
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
All in-person participant visits will take place in the Center for NMR Research. Urine and saliva 
specimens will be stored, processed and analyzed in the Biomarkers and Analytical Chemistry Core 
(BACC) laboratory on the 3rd floor of the Cancer Institute or sent to another Biosafety approved HMC 
laboratory if the BACC does not have capacity. These laboratories will not charge participants or 
insurance organizations for analysis procedures.    
 

Page 24 of 31 (V.04/27/2017) 
16.2 
Feasibility of recruiting the required number of subjects 
The smoking prevalence in South Central Pennsylvania is 19% of the adult population and approximately 
40% of these smokers have no current plan to reduce or quit smoking. Penn State has been conducting 
clinical trials of new tobacco products for four years and has amassed a database of thousands of 
smokers interested in research participation (Study# 0002213). With the use of this database we expect 
to recruit 90 subjects over four years. 
 
16.3 
PI Time devoted to conducting the research 
Dr. Hobkirk has 75% protected time for research through a NIDA K23 Award, of which this is the primary 
project. The majority of her time is devoted to research, including this project. The rest of the research 
team will also have appropriate percent times covered by this grant or Departmental funds. 
 
16.4 
Availability of medical or psychological resources 
All of our participants will be seen by appropriately trained research staff. Any serious AEs or concerning 
test results will be passed on to participants along with a letter to their doctor as requested. We do not 
anticipate any urgent psychological distress requiring psychological care; however, Dr. Hobkirk is a 
licensed clinical psychologist and will evaluate patients and refer to appropriate emergency mental 
health resources as necessary. Any urgent health problem will require accompanying the participant to 
the ER. 
 
16.5 
Process for informing Study Team 
At least monthly team meetings will be conducted where study procedures, questions and issues will be 
discussed and resolved. In addition regular project meetings will be held to discuss study progress with 
the research staff. 
 
17.0 Other Approvals 
 
17.1 
Other Approvals from External Entities 
Per federal regulations, an Investigational Tobacco Product (ITP) application was submitted and 
approved by the FDA. A Certificate of Confidentiality is issued automatically for this NIH-funded project. 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library. 
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy).  
 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.   

Page 25 of 31 (V.04/27/2017) 
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 
 
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
18.0 Multi-Site Research 
N/A 
 
18.1 
Communication Plans 
 
18.2 
Data Submission and Security Plan 
 
18.3 
Subject Enrollment 
 
18.4 
Reporting of Adverse Events and New Information 
 
 
18.5 
Audit and Monitoring Plans 
 
19.0 Adverse Event Reporting 
 
19.1 
Adverse Event Definitions 
 
For drug studies, incorporate the following definitions into the below responses, as written: 
Adverse event 
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related 
Adverse reaction 
Any adverse event caused by a drug 
Suspected adverse 
reaction 
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”. 
• 
Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
Serious adverse 
event or Serious 
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 

Page 26 of 31 (V.04/27/2017) 
suspected adverse 
reaction 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction 
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death. 
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.   
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified. 
 
 
 
For device studies, incorporate the following definitions into the below responses, as written: 
Unanticipated 
adverse device 
effect 
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
19.2 
Recording of Adverse Events 
Research subjects will be routinely questioned about adverse events at in person study visits.  
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study cigarettes will be followed until the event (or its sequelae) 
or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator.  
 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met: 
1) The test finding is accompanied by clinical symptoms 
2) The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other therapy 
Note: Simply repeating a test finding, in the absence of any of the other listed criteria, does 
not constitute an adverse event. 
3) The test finding leads to a change in study drug dosing or discontinuation of subject participation in 
the clinical research study 
4) The test finding is considered an adverse event by the investigator. 
 
19.3 
Causality and Severity Assessments 
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event. 
 

Page 27 of 31 (V.04/27/2017) 
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
cigarettes for reporting purposes. If the investigator’s final determination of causality is “unknown but 
not related to the study cigarettes”, this determination and the rationale for the determination will be 
documented in the respective subject’s case history. 
 
19.4 
Reporting of Adverse Reactions and Unanticipated Problems to the FDA   
 
19.4.1 Written IND/IDE Safety Reports 
N/A 
 
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions 
N/A 
 
19.5 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 
19.6 
Unblinding Procedures 
If an adverse event requires the subject to be unblinded, the unblinded study personnel (cigarette 
administrator) will be able to provide that information as needed. Otherwise, participants will not be 
unblinded to their cigarette allocation. The principal investigator will begin by reviewing the protocol 
and establishing guidelines for data and safety monitoring including any additional procedures for 
unblinding of participants. 
 
19.7 
Stopping Rules 
The principal investigator will also develop trial stopping rules to help define the point at which the risks 
to subjects of continuing the study outweigh the likely benefits. A brief report will be generated and 
provided to the Penn State IRB. 
 
20.0 Study Monitoring, Auditing and Inspecting 
 
20.1 
Study Monitoring Plan  
 
 
20.1.1 Quality Assurance and Quality Control 
Data will be collected from participants and coded directly by either using the REDCap survey 
tool (participant entered data) or through REDCap data entry forms (researcher entered data). 
The codes that link the name of the participant and the study ID will be kept confidential in 
REDCap. Any paper forms (consent) will be securely transported to the PI’s data entry center. 
Any additional data that is generated will be stored electronically on the Department server in 
password protected files.  
 
Study data will be managed using REDCap (Research Electronic Data Capture). REDCap is a 
secure web application designed to support data capture for research studies, providing user-
friendly web-based case report forms, real-time data entry validation (e.g. for data types and 
range checks), audit trails and a de-identified data export mechanism to common statistical 
packages (SPSS, SAS, Stata, R/S-Plus). The system was developed by a multi-institutional 
consortium which includes The Pennsylvania State University and was initiated at Vanderbilt 
University. The database is hosted at the Penn State Hershey Medical Center and College of 

Page 28 of 31 (V.04/27/2017) 
Medicine data center, which will be used as a central location for data processing and 
management. REDCap data collection projects rely on a thorough study-specific data dictionary 
defined in an iterative self-documenting process by all members of the research team. This 
iterative development and testing process results in a well-planned data collection strategy for 
individual studies. REDCap is HIPAA compliant. Data are stored on a secure server; data in 
REDCap are encrypted; access to the database requires authentication (a unique username and 
password); data are accessed based on the individual’s role on the project; every interaction 
with the data is logged, creating an audit trail. Random data entry checks will be implemented 
regularly to identify problems with data entry. Data quality tools included in REDCap will be 
utilized to identify incorrect data types, out of range data and outliers. In addition, electronic 
edit checks, and random internal quality and assurance checking will be performed manually. 
Data quality will be monitored by random inspection of the completed electronic forms by one 
of the research assistants or principal investigator and any problems detected will be discussed 
with the PI. If necessary, re-training of researchers will be conducted. The responsibility for data 
quality and study conduct lies with the PI. Site visits will be conducted by the Penn State 
research team to ensure that procedures are being executed in compliance with the protocol, 
and IRB policies. 
 
20.1.2 Safety Monitoring 
The principal investigator will monitor the safety of study participants. The Principal Investigator 
will confirm that all adverse events (AE) are correctly entered into the AE case report forms by 
the coordinator; be available to answer any questions that the coordinators may have 
concerning AEs; and will notify the IRB, FDA, and sponsor of all applicable AEs as appropriate. 
We will consult licensed medical professional at the Penn State College of Medicine and the 
project faculty mentors as needed. The research coordinator will ensure that AEs are correctly 
entered into REDCap and complete the appropriate report form and logs; assist the PI to 
prepare reports and notify the IRB, and FDA of all Unanticipated Problems/SAE’s. 
21.0 Future Undetermined Research: Data and Specimen Banking 
 
21.1 
Data and/or specimens being stored 
Saliva collection specimens will be stored with an ID code and date of collection attached. Storage and 
processing will be tracked in REDCap.  
21.2 
Location of storage 
Specimens will be stored in a locked freezer room in the research laboratory of Drs. Muscat and Richie 
on the 3rd floor of the Cancer Institute, the Department of Psychiatry on the 5th floor of the College of 
Medicine, or in the Department of Pediatrics on the 7th floor of the College of Medicine.  
21.3 
Duration of storage 
Specimens will be stored indefinitely with code number attached. Data will be stored indefinitely with 
identifiers attached in REDCap.  
21.4 
Access to data and/or specimens 
The lab managers, technicians, study coordinators and PI will have access to the freezer rooms where 
the specimens will be stored. The researchers will have access to the stored data in REDCap although 
role specific rights will be granted to forms (i.e., researchers who see participants will not have access to 
data that may allow them to become unblinded to a participant’s treatment allocation).  
21.5 
Procedures to release data or specimens 
Investigators interested in obtaining samples from this project for ancillary studies will first be required 
to submit a detailed written proposal to the principal investigator. The investigator will then need to 
obtain all other regulatory approvals (IRB, departmental scientific committees, etc.) prior to samples 
being released to the investigator.  

Page 29 of 31 (V.04/27/2017) 
21.6 
Process for returning results 
Investigators will be required to provide a written report on their study results to the principal 
investigator. Individual participants will not be provided with the results of the analyses of their 
samples.  
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