Reduced Nicotine Cigarettes in Smokers With Mood and Anxiety Disorders
Phase: NA
Conditions: Tobacco Dependence
Sponsor: Milton S. Hershey Medical Center

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Protocol for
Human Subject Research
with Use of Test Article(s)
Protocol Title: Reduced Nicotine Cigarettes in Smokers with Mood and Anxiety 
Disorders
Principal Investigator:
Jonathan Foulds, PhD
Public Health Sciences
717-531-3504
jfoulds@psu.edu
Version Date:   1-10-19
Clinicaltrials.gov Registration #:  NCT01928758
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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
Data and Specimen Banking For Future Undetermined Research
9.0
Statistical Plan
10.0
Confidentiality, Privacy and Data Management
11.0
Data and Safety Monitoring Plan
12.0
Risks
13.0
Potential Benefits to Subjects and Others
14.0
Sharing Results with Subjects
15.0
Economic Burden to Subjects
16.0
Number of Subjects
17.0
Resources Available
18.0
Other Approvals
19.0
Subject Stipend (Compensation) and/or Travel Reimbursements
20.0
Multi-Site Research
21.0
Adverse Event Reporting
22.0
Study Monitoring, Auditing and Inspecting
23.0
References
24.0
Appendix
1.0
Objectives
1.1
Study Objectives
Tobacco smoking is the leading preventable cause of premature morbidity and mortality in the United 
States [1], and cessation provides immediate and sustained improvement in health and quality of life 
[2]. Nicotine is the primary addictive substance in cigarettes, and cigarettes smoked in the United 
States typically contain an average of 11 mg of nicotine [3-5]. It should be noted that the nicotine 
content of a cigarette is a different concept than the “nicotine yield” as measured by a smoking 
machine, and which was previously printed on cigarette packs. It is now known that the main factor 
affecting the machine-smoked nicotine yield in current commercially available cigarettes is the amount 
of ventilation in the filter. For example the brands formerly known as “Marlboro Lights” actually 
contained almost an identical amount of nicotine as regular Marlboro Reds (11mg), but had more 
ventilation holes in the filter. It is now known that smokers smoke highly ventilated (low nicotine yield) 
cigarettes differently from regular cigarettes, and end up absorbing almost as much nicotine and 
toxicants by increasing puff frequency and volume. It is partly for this reason that the terms “Light” and 
“Mild” are no longer allowed. The Family Smoking Prevention and Tobacco Control Act [6] gave the 
FDA jurisdiction to regulate tobacco products, including the nicotine content of cigarettes. Progressive 
reduction of the nicotine content of cigarettes to very low levels is a potential way to reduce the 
addictiveness of cigarettes, and may help established smokers to quit smoking [7, 8]. Preliminary 
studies have found that progressive reduction of nicotine content of cigarettes is feasible and safe in 
smokers without comorbid psychiatric illness [8-11]. However, it is not known whether progressive 
nicotine reduction is feasible and safe in the large subgroup of smokers with comorbid psychiatric 
illness. Smokers with psychiatric illnesses purchase over 40% of cigarettes sold in the US [12], have a 
higher prevalence of smoking, greater severity of nicotine dependence and lower cessation rates than 
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smokers without comorbid psychiatric illness [12, 13]. Smokers with a prior mood or anxiety disorder 
report more severe nicotine withdrawal symptoms during a cessation attempt [14, 15]. This suggests 
the possibility of more difficulty switching to very low nicotine content cigarettes, and potentially more 
compensatory smoking of lower nicotine content cigarettes that could increase exposure to other toxins 
in tobacco smoke [16, 17]. On the other hand, if smokers with mood and anxiety disorders can safely 
transition to significantly reduced nicotine content cigarettes, it is plausible that further progression to 
smoking cessation may be more achievable from a lower level of nicotine dependence. Prior to 
implementation of progressive nicotine reduction on a national level, it is important to establish the 
feasibility and safety of this approach in this subgroup of smokers. 
The overall aim of this proposed study is to evaluate the effect of progressive nicotine reduction 
in cigarettes on smoking behavior, toxicant exposure and psychiatric symptoms in smokers 
with comorbid mood and/or anxiety disorders. To do so, we will randomly assign adult smokers with 
a history of unipolar mood and/or anxiety disorder to smoke research cigarettes that will contain either 
a) Usual Nicotine Content (UNC):  nicotine content (11.6mg) similar to popular brands of cigarettes; or 
b) Reduced Nicotine Content (RNC):  the nicotine content per cigarette is progressively reduced from 
approximately 11.6 mg to 0.2 mg over 5 months. All subjects will participate in lead-in periods prior to 
randomization to assess normal smoking behavior and to establish ability to tolerate research 
cigarettes prior to randomization.  It is our hypothesis that nicotine intake, as measured by plasma 
cotinine concentration, will decline as a function of cigarette nicotine content in the RNC group. Further, 
it is our hypothesis that by gradually reducing the nicotine content of the cigarettes in three week steps, 
there will not be significant increases in biomarkers of tobacco smoke exposure, severity of nicotine 
withdrawal symptoms, mood and anxiety symptomatology or protocol non-adherence over time in the 
experimental group (RNC) as compared with the UNC control group. 
Aims:
1. To assess the effect of switching to gradually reduced nicotine content cigarettes on product 
use patterns and biomarkers of exposure in smokers with mood and/or anxiety disorders. 
Hypothesis 1.a.:  Smokers assigned to the RNC group will have lower plasma cotinine 
concentrations during the last 3 weeks of the randomized phase of the study than those 
assigned to the UNC group.
Hypothesis 1.b.: There will be no significant increase in key markers of tobacco use (e.g. 
cigarette consumption), biomarkers of tobacco smoke exposure (e.g. NNAL, CO), or health 
effects (e.g. blood pressure) in those assigned to the RNC group vs. those assigned to UNC. 
2. To assess the effect of switching to gradually reduced nicotine content cigarettes on 
psychiatric and nicotine withdrawal symptoms in smokers with unipolar mood and / or anxiety 
disorders. 
Hypothesis 2: There will be no significant increase in ratings of psychiatric or nicotine 
withdrawal symptoms in those assigned to the RNC group as compared to those assigned to 
UNC.
3. To assess the effect of switching to gradually reduced nicotine content cigarettes on self-
perception of tobacco dependence, self-report of intention to quit smoking, and actual smoking 
cessation.
Hypothesis 3: Among smokers who complete the  randomized nicotine reduction phase, 
smokers assigned to the RNC group will have lower perceived dependence, be more likely to 
report intention to quit smoking, and be more likely to make a smoking cessation attempt and 
achieve cigarette abstinence at visit 12..
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1.2
Primary Study Endpoints
Plasma cotinine concentrations during the last 3 weeks of the randomized nicotine reduction 
phase (visit 10).
1.3
Secondary Study Endpoints 
Biomarkers of tobacco smoke exposure (e.g. NNAL, CO), cigarette consumption, health effects 
(e.g. blood pressure) and mental health measures (e.g. nicotine withdrawal, perceived stress, 
QIDS, Kessler K6).
The proportion of each group making a choice to try to quit smoking will be an endpoint, as will 
the proportion succeeding in quitting successfully during the choice phase.  Intent to treat (ITT) 
abstinence (based on the assumption that a loss-to-follow-up subject resumes smoking) and 
completers’ abstinence (based on the assumption that the probability of loss to follow up is 
independent of smoking status) will be analyzed. Abstinence will be biochemically verified (CO 
< 10ppm). 
2.0
Background 
2.1
Scientific Background and Gaps
Reducing nicotine content in cigarettes: This approach has the potential to significantly 
reduce the public health harm from tobacco dependence. However, the impact of reduced 
nicotine cigarettes on smoking behavior, toxicant exposure and cessation needs to be assessed 
empirically prior to implementation of a national nicotine reduction policy [7].  The primary 
concern about a progressive nicotine reduction strategy is that it may have the unintended 
consequence of compensatory increase in tobacco smoke exposure as nicotine content in 
cigarettes is reduced (if smokers smoke more cigarettes per day, inhale more smoke per 
cigarette, or both) [16]. It has been postulated that compensatory smoking of reduced nicotine 
cigarettes may change the way cigarettes are smoked in a manner that results in increased 
toxicant exposure, even if compensation (with respect to nicotine extraction) is incomplete [17]. 
This could occur, for example, by changes in the puffing patterns causing changes in the 
temperatures achieved in the rod and tip of the cigarette and consequent changes in the 
chemicals inhaled by the smoker.
2.2
Previous Data
Early studies of the behavioral effects of a progressive nicotine reduction strategy have been 
encouraging.  A series of studies by Benowitz and colleagues [9-11] examined the effects of a 
progressive nicotine reduction strategy in which smokers switched to cigarettes with 
progressively lower nicotine content (or yield) over 4 weeks or 6 months. In their initial study of 
20 smokers, gradual reduction of nicotine content was feasible and did not increase apparent 
exposure to tobacco smoke toxins [9]. In a follow up study [10], 135 otherwise healthy smokers 
were randomly assigned to one of two groups: (a) an experimental group that smoked their 
usual brand followed by research cigarettes with progressively reduced nicotine content (RNC 
over five, month-long steps), or (b) a control group that continued smoking their own brand of 
cigarettes for the entire study period. In the smokers assigned to RNC cigarettes, nicotine 
intake, as assessed by plasma cotinine concentration, declined progressively as the nicotine 
content of the cigarettes was reduced, while toxin exposure remained stable or, in the case of 
the carcinogen, NNAL, was reduced. The titration was well tolerated, but smokers assigned to 
the RNC group reported decreased “vigor” scores and increased “confusion” scores on the 
Profile of Mood States (POMS) during the time they were smoking 2mg and 1mg nicotine 
content cigarettes (compared with baseline), and smokers assigned to the RNC group who were 
adherent to study procedures also had a 2kg increase in body weight during the study period. 
These effects are consistent with nicotine withdrawal effects [18].  Importantly, significantly more 
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of the RNC group (51%) than the control group (14%), were interested in quitting smoking by 
the end of the tapering period. These studies [8-10, 19, 20] demonstrate that a progressive 
nicotine reduction strategy is feasible, results in reduced nicotine exposure, increases desire to 
quit smoking and does not result in increased exposure to other toxicants.
These studies have been well conducted, clear in their conclusions and represent a critical first 
step in the process of empirically evaluating the effects, intended or unintended, of a policy of 
progressive nicotine reduction in cigarettes. However, there are some issues regarding 
generalizability of the results that must be evaluated prior to implementation of such a policy. A 
large proportion (>40%) of cigarettes sold in the United States are sold to someone with a 
current psychiatric illness, and smoking prevalence is demonstrably higher among those 
groups. However, enrollment in the studies conducted to date has focused on relatively well-
educated, otherwise healthy smokers. In the most recent study[10], 35% of those screened 
were excluded for current drug or alcohol dependence and 20% for other health issues, and 
those enrolled had an average of 15 years education. Further, there was differential drop out for 
those with more severe nicotine dependence as evidenced by higher baseline Fagerstrom Test 
for Nicotine Dependence (FTND) scores.
Studies of potentially modified risk tobacco products to date have measured a range of 
biomarkers, but have tended to focus on certain reliable key measures of nicotine exposure 
(e.g. cotinine), smoke exposure (e.g. exhaled carbon monoxide), and carcinogen exposure (e.g. 
NNAL). These markers have the advantages of being well validated, are relatively specific to 
tobacco smoking, and change relatively quickly in response to changes in exposure(39). 
However, tobacco products are a major cause of oxidative stress and evaluation of the potential 
risks of different tobacco products should include measurement of biomarkers of oxidative 
stress. Tobacco smoke is an abundant source of free radicals, containing over 1017 reactive 
oxygen and nitrogen species (ROS/RNS) per puff and considerable evidence indicates that 
these agents play fundamental roles in the development of many of the major smoking-caused 
diseases including cancer, COPD and heart disease (1). Our team has pioneered the use of 
certain measures of oxidative stress, including demonstrating differences between levels in 
cigarette smokers and non-smokers (40), and demonstrating relationships between these 
measures and tobacco-related cancer (41). We therefore propose to extend that line of 
research, by assessing three measures of oxidative stress at baseline and during the 
randomized portion of our proposed trial. We believe this will be the first time that valid 
biomarkers of oxidative stress will be assessed in a randomized trial of RNC cigarettes.
2.3
Study Rationale
Approximately one-third of adult smokers in the U.S. had a mental disorder in the past 12 
months, compared with less than one in five non-smoking adults [21]. Twenty three percent of 
adult smokers have a comorbid anxiety disorder and 13% have a comorbid mood disorder [21]. 
Among nicotine dependent smokers, 22% have a mood disorder and 23% have an anxiety 
disorder (compared with 7% and 10% of nonsmokers) [22]. Smokers with a comorbid 
psychiatric illness may be more vulnerable to unintended effects of a progressive nicotine 
reduction policy at the national level. These smokers, by the nature of their comorbid psychiatric 
illness, experience chronic high levels of psychological distress, and may be more likely to 
exhibit compensatory smoking behavior in order to maintain systemic nicotine concentrations. 
Smokers with mental illnesses report wanting to quit smoking, trying to quit smoking, and use of 
smoking cessation aids at similar rates to people without mental health problems, but may be 
less likely to succeed when they attempt to quit smoking [21, 23]. 
The reasons for the well-established, high prevalence of comorbid mood and anxiety disorders 
in those with nicotine dependence are complex and not fully understood. One of the most basic 
reasons may be that nicotine withdrawal symptoms such as anxiety and depression may be 
harder to cope with for those already suffering related disorders. Many studies have found that 
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smokers with anxiety disorders report elevated nicotine withdrawal symptoms during early 
abstinence, compared to those without [15, 24-26]. Potential mechanisms have been identified 
but remain uncertain. For example, smokers with a prior major depressive episode have greater 
smoking-induced brain dopamine release than those without such a history [27]. Non-nicotine 
constituents in cigarette smoke may also be involved. Monoamine oxidase A (MAO-A) is a brain 
enzyme that modulates mood because it metabolizes monoamines, including dopamine. During 
tobacco abstinence, heavy smokers experience an increase in brain MAO-A. This effect, which 
covaries with severity of depression, suggests one possible biological mechanism for worsening 
of depressed mood during withdrawal from cigarette smoking [28].
For the reasons described above, smokers with mood and anxiety disorders may be particularly 
vulnerable to unintended effects of a policy of progressive nicotine reduction in cigarettes. It is 
not known if smokers with these conditions are more likely to “oversmoke” reduced nicotine 
cigarettes and experience increased toxin exposure as a result. It is also possible that smokers 
with mood and anxiety disorders may experience some exacerbation in their psychiatric 
symptoms as they gradually withdraw from nicotine under a nicotine reduction policy. On the 
other hand, if smokers with mood and anxiety disorders can safely transition to significantly 
reduced nicotine content cigarettes, it is plausible that further progression to smoking cessation 
may be more achievable from a lower level of nicotine dependence. We therefore propose to 
examine the effects of switching to reduced nicotine content cigarettes in smokers with current 
or past anxiety and mood disorders. We see this as a critical test of the feasibility of the RNC 
regulatory strategy.
3.0
Inclusion and Exclusion Criteria 
3.1
Inclusion Criteria
1.
Aged 18 - 65
2.
Smoke >4 cigarettes/day for at least the past 12 months 
3.
No quit attempt in prior month and not planning to quit smoking within next 6 months (to 
ensure stability of smoking)
4.
Plan to live in local area for next 8 months
5.
Meet DSM-V lifetime diagnostic criteria for a current or lifetime Anxiety Disorder (Panic 
disorder, agoraphobia, social phobia, obsessive compulsive disorder, post-traumatic stress 
disorder, generalized anxiety disorder)  or  a unipolar Mood Disorder (e.g. Dysthymia, Major 
Depression,) based on MINI (Mini International Neuropsychiatric Interview) structured 
interview 
6.
Women not pregnant or nursing and taking steps to avoid pregnancy 
7.
Able to understand and consent to study procedures 
8.
Read and write in English 
9.
No members of the household currently involved in any trial related to reduced nicotine 
cigarettes
10. Participants who become subject to correctional supervision through probation, parole, 
home confinement, electronic monitoring, work release or other monitored, non-custodial 
supervision after signing the consent form.
Notes related to prisoner participation:  The prisoner participant must be permitted by their 
probation/parole officer, court or other authority to go to the research office visits, and any 
monitoring devices need to be programmed to reflect that additional time/place of travel.  
These issues will be resolved by the prisoner and their supervising authority on a case-by-
case basis.
Rationale to include prisoners:  Potential benefit of the subject (intent and reasonable 
probability of improving the health or well-being of the subject).
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3.2
Exclusion Criteria
1.
Unstable or significant medical conditions and conditions such as elevated blood pressure 
(Systolic >160 mm Hg at baseline), COPD or kidney failure and those that are likely to affect 
biomarker data
2.
Use of non-cigarette nicotine delivery product in the prior week (including cigars, pipes, 
chew, snus, hookah, electronic cigarette and marijuana)
3.
Currently reducing or planning to reduce cigarette consumption in next month.
4.
Use of a smoking cessation medicine in prior month (any nicotine replacement, varenicline, 
bupropion)
5.
Uncontrolled serious psychotic illness (includes diagnosis of schizophrenia, bipolar disorder, 
eating disorder, and dementia) or inpatient treatment for a mental health condition in the 
past 6 months 
6.
More than weekly use in the past 3 months of illegal drugs or prescription drugs that are not 
being used for medically prescribed purposes or inpatient treatment for these in the past 6 
months 
7.
Alcohol use that would hinder the participant’s ability to participate. 
8.
Current suicide risk on clinical assessment (above “low risk” score on MINI diagnostic 
interview)
9.
Unwillingness to provide blood samples or history of repeatedly fainting during blood draws 
10. Unwilling to remain on one flavor of cigarette (regular or menthol) for the duration of the trial 
or smokes hand-rolled cigarettes
11. Any other condition or situation that would, in the investigator’s opinion, make it unlikely that 
the participant could comply with the study protocol.
12. Those who are prisoners at the time of enrollment.
13. Those who become custodial inmates at any correctional facility after enrollment in the 
research.
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Participant withdrawal prior to randomization (Baseline I and II)
Baseline Phase I and II have been designed to identify participants who are not able or 
willing to comply with the full study protocol after randomization. During Baseline I, 
participants will smoke their own usual brand of cigarettes for 1 week. At Baseline II, all 
participants will be asked to smoke research cigarettes with a normal amount of nicotine 
(around 11mg).  Participants who are removed prior randomization will be replaced until 
a total of 200 participants have been randomized (100 at the Hershey site and 100 at 
Mass. General Hospital).  
 At any time prior to randomization participants will be withdrawn from the study if:
1.
They report using non-cigarette nicotine products at more than one visit.  This 
includes any number of cigars, pipes, snuff, chew, hookah, electronic cigarette, 
marijuana, or any other illegal smoked substance.
During Baseline II only, participants will be withdrawn from the study if:
1.
Participant’s total cigarette consumption includes more than 10% of non-
research cigarettes in the 6 days prior to visit 4 only (Average cigarettes from day 
15-20,  e.g. 4 or more out of 30 cigarettes in 6 days for a 5 cpd smoker; 18 or more 
out of 180 cigarettes in 6 days for a 30 cpd smoker).
2.
Participant has reduced their cigarette consumption by more than 50% from 
baseline (when cigarettes per day are averaged over days 15-20).  
3.
Significant baseline smoking rate increase:  A participant will be withdrawn from 
the study if they meet BOTH of the following criteria:
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a.
The average cigarette per day (CPD) increase by more than 100% from the 
average CPD at the Baseline I assessment (visit 1) when calculated over the 
previous 6 days.  
b.
The average of two consecutive expired breath carbon monoxide 
measurements increase according to the following: 
i.
CO is greater than 50 ppm if CO at assessment visit 1 is <20 ppm.
ii.
CO is greater than 60 ppm if CO at assessment visit 1 is 20 – 34 ppm.
iii.
CO is greater than 70 ppm if CO at assessment visit 1 is 35 – 49 ppm.
iv.
CO is greater than 80 ppm if CO at assessment visit 1 is 50 – 60 ppm.
v.
CO is greater than 90 ppm if CO at assessment visit 1 is 61 – 70 ppm.
Participants may be discontinued by the investigator at any point during the study for any 
of the following reasons:
•
Pregnancy (confirmed by urinary pregnancy test every 4-8 weeks. See Time and 
Events table).  
•
High risk of suicide based on MINI Suicide module or has made a suicide attempt
•
Elevated blood pressure at any visit (Systolic >160 mmHg).
•
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 starting at visit 4 as described above 
and ending when participant is no longer receiving research cigarettes.  Either 
one, or both criteria combined:
o
The average CPD increases by more than 100% from the average CPD 
at the baseline assessment visit. 
o
Expired breath carbon monoxide increases, as described above 
•
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.  This could include recovery from a major surgery, worsening 
of psychiatric symptoms, etc.)
•
For any missed visit where the participant would have received new research 
cigarettes, participants will be reviewed and considered for withdrawal on a case 
by case basis.  
•
Any situation where participant is not able to smoke research cigarettes for a 
period of more than 2 consecutive weeks
•
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
If participants are withdrawn from the study for any of the reasons noted above during 
Baseline I or II (prior to randomization), they will be replaced until a total of 200 
participants have been randomized to the study. Subjects who voluntarily withdraw from 
the study will be asked to complete a questionnaire regarding the reasons for dropping 
out and what they didn’t/did like about the study.  
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4.0
Recruitment Methods
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 calling the study center number will first complete the eligibility script and 
questions for IRB Protocol #2213. If a participant’s responses match our study’s specified 
inclusion criteria they will be forwarded to our study’s coordinator for further screening.  
4.3
Recruitment materials
All study materials for this project will be approved through IRB Protocol #2213.  To summarize, 
materials in that project include letters, newsletters, flyers and radio/print text. Participants will 
be recruited from the Harrisburg/Hershey/Lancaster community by using the following 
resources:
a) Media advertisements (newspaper, radio, internet)
b) Study posters/flyers placed on community message boards and in local businesses, 
medical clinics
c)
Community newsletters including the Hershey Medical Center employee newsletter
d) Newsletters/letters sent to past study participants who consented to being contacted 
about future research
e) Internet locations including but not limited to:
i.
HMC Facebook page
ii.
Penn State TCORS website
iii.
Craigslist
.
4.4
Eligibility/screening of subjects
1.
Screening 1 (phone): We will consider the screening process and eligibility questions in 
IRB protocol #2213 as Screening 1.  This process includes a brief phone screening to 
determine basic eligibility for any of our study center protocols.  Then, participants will 
complete the screening for this study in two additional steps. 
2.
 Screening 2 (phone):  A full script and screening questions for this study are in the 
“Consent Forms and Recruitment Materials” section of the IRB application.
3.
Screening 3 (In person, Visit 1):  After a participant has met basic eligibility criteria over 
the phone, they will be scheduled to come into the study center where they will be 
consented to the study and further screened for eligibility. See section 7.2 for further details.   
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
When participants attend their first in person assessment visit, they will have 
the study explained to them in detail, have the opportunity to ask questions 
and then will be asked to sign the consent form.  Participants will be given a 
signed copy of the form.  This will take place in a private clinic room at the 
Penn State CTSI.
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 
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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
5.2
Consent Documentation
5.2.1
Written Documentation of Consent
An IRB approved consent form will be used to document consent.  Both the researcher 
and the participant will retain a copy of the consent.  The participant’s signed consent 
form will be periodically uploaded into the participant’s REDCap record at the Hershey 
site.  Harvard/Mass General will store their consents in a locked filing cabinet in a 
locked research office.
5.2.2
Waiver of Documentation of Consent
Participants who are interested in the study will be asked to consent to allow the 
researcher to pre-screen them for the study over the phone by asking all screening 
questions of all participants (eligible or ineligible).  Participants will be asked if this 
information can be retained so that the study team will know reasons that participants 
are not eligible for the study.
In addition, participants who are not eligible for the study, or those who begin the phone 
screener 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 
5.3.1
Non-English Speaking Subjects
Non-English speaking subjects will not be eligible for this study because all study visits 
and materials need to be conducted/provided in English.
5.3.2
Cognitively Impaired Adults
Cognitively impaired adults will not be eligible for this study.
5.3.2.1 Capability of Providing Consent
N/A
5.3.2.2 Adults Unable To Consent
N/A
5.3.2.3 Assent
N/A 
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
5.3.3.1 Parental Permission
N/A
5.3.3.2 Assent
N/A
6.0
HIPAA Research Authorization and/or Waiver or Alteration of 
Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures 
of PHI
Check all that apply:
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
Authorization will be obtained and documented as part of the consent process.
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)
Full waiver is requested for entire research study (e.g., medical record review studies) 

Alteration is requested to waive requirement for written documentation of authorization
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
All data collected during the screening process will be directly entered into 
REDCap.
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
All study data will be retained indefinitely.
6.2.2
Explanation for why the research could not be practicably be conducted without 
access to and use of PHI
N/A
6.2.3
Explanation for why the research could not practicably be conducted without the 
waiver or alteration of authorization
In order to screen the participants prior to inviting them into the study center, the 
investigators are conducting a phone screen to determine if the participants are likely to 
be eligible for the study.
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 that will proceed in three phases 
over 33weeks.  Participants and study staff will be blind to the experimental cigarette allocation 
until the end of the last visit. Visits will occur at consistent times during the day, when possible.  
For participants who do not show up for scheduled study visits up to 5 attempts will be made to 
contact them to reschedule their appointment.  After the 5th attempt, a letter will be sent to the 
address on file informing them that the study team has been trying to reach them and asking 
them to contact the study center to reschedule.  No further attempts to contact the participant 
will be made after the letter is sent (see study documents for letter).
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1.
Baseline Phase:
Baseline I: participants will smoke their own usual brand of cigarettes for 1 week. 
Baseline II: all participants will be asked to smoke research cigarettes containing a 
normal amount of nicotine (11mg) and  matching the flavor (regular or menthol) of their 
usual brand of cigarettes for 2 weeks. 
2.
Randomized Double-Blind Nicotine Reduction Phase (18 weeks),  participants who 
complete Baseline II and agree to continue will enter this phase. They will be randomized to 
either (1) continue to smoke the same research cigarettes they smoked in Baseline II for 18 
weeks with their usual nicotine content (UNC) or (2) switch to progressively reduced nicotine 
content (RNC) cigarettes over 18 weeks. 
3.
Treatment Choice Phase (12 weeks)
Prior to making their “Treatment Choice”, all participants will receive a copy of the Surgeon 
General Report, “How Tobacco Causes Disease” and resources they can contact for help. 
Regardless of the participant’s choice, all participants will attend two additional follow up 
visits 4 weeks (visit 11) and 12 weeks (visit 12) after the end of the randomized phase.
Choices that will be provided to the participant include:
1.
Return to their usual brand
2.
Continue on the research cigarettes for a further 12 weeks (provided at no cost)
3.
Receive assistance to quit smoking (with counseling and short acting nicotine 
replacement therapy medication provided at no cost) for 11 weeks.
7.2
Study Procedures
Screening [Day 0]
After a participant has met basic eligibility criteria over the phone, they will be scheduled to 
come into the study center where they will be consented to the study and further screened for 
eligibility.
Informed consent will be obtained by research staff. During this process, the usual discussion of 
procedure, risks, side effects, confidentiality, voluntary participation, and right to refuse 
participation without prejudice will be explained to the participant. Participants must be capable 
of understanding the nature of this study, its potential risks, discomforts and benefits before 
signing consent.  
Measures and Procedures:
The following information will be collected to determine eligibility:
1.
NIDA Drug Screener (not eligible if any drugs are used weekly or more)
2.
Medical history
3.
Concomitant medication history to ensure that the participant is not taking any medications 
that may make them ineligible for the study
4.
Measure vital signs.  (inclusion systolic <160) 
5.
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
6.
Complete the MINI (inclusion=positive current or lifetime diagnosis for mood or anxiety 
disorder), MINI Suicide score is < 9
Procedure for suicide risk at screening:  Scores of > 9 on the MINI Suicide module will 
require an assessment with a licensed clinician to document a clinical plan. Participant with a 
score >8 will not continue in the study unless judged to be stable and not at high risk for suicide.
Baseline I (1 week on own brand of cigarettes)
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After a participant is determined to be eligible for the study, they will complete the 
questionnaires, biomeasures and procedures outlined in the time and events table.  
The following procedures will be conducted at all Baseline visits:
•
Participants will be instructed on standard study procedures, online surveys, phone calls 
and on how to use the study cigarette log, will be given a supply of logs and small 
pencils, and will be asked to log the total number of cigarettes they smoke each day.  
The participants will be given the opportunity to ask any questions they may have 
regarding keeping their log.  
•
The participant and a member of the study staff will review a preliminary schedule of 
study visits, dates and times. Any scheduling conflicts will be resolved and the 
participant provided with a new schedule of visits. The importance of keeping on 
schedule with appointments will be discussed.
•
Participant will strongly advised not to use other forms of tobacco or marijuana.  
Participants will also be asked to honestly report any other tobacco or marijuana use at 
subsequent visits.
• Participants will be asked to rate their confidence in complying with the study protocol on 
a scale from 1-10, with 1 being no confidence and 10 being complete confidence.  Any 
scores < 6 will prompt the researcher to troubleshoot any challenges identified by the 
participant.
Procedure for suicide risk at all visits where QIDS questionnaire is administered:  If 
participants indicate an answer of > 0 on item 12 of the QIDS questionnaire, the MINI 
Suicide module will be administered.  Scores of > 9 on the MINI Suicide module will require 
an assessment with a licensed clinician to document a clinical plan and a determination of 
retention or termination from the study.
Time and Events Table 
Baseline
Randomization
   
Baseline I
Baseline II
Step 
1
Step 
2
Step 
3
Step 
4
Step 5
Treatment 
Choice
Study Week Number
1
2
3
4
7
10
13
16
19
22
26
34
Study Day
1
8
15
22
43
64
85
106
127
148
176
232
 Study Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Measures/Questionnaires
Tobacco and marijuana use and 
daily cigarette log*
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications*
X
X
X
X
X
X
X
X
X
X
X
Adverse events*
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Tobacco use history, cigarette 
details*
X
NIDA drug use (past 3 mo)
x
X
X
Environmental smoke 
questionnaire
X
X
X
X
X
X
X
X
X
X
Perceived health risk
X
X
X
X
X
X
Cigarette liking scale
X
X
X
X
X
X
X
X
X
X
Nicotine dependence (HONC, 
FTND, PSU)
X
X
X
X
X
X
X
X
X
X
X
X
Minnesota withdrawal scale
X
X
X
X
X
X
X
X
X
X
X
X
Questionnaire smoking urges
X
X
X
X
X
X
X
X
X
X
X
Audit-C
X
X
X
X
X
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Visit 1 [Day 1]
Cigarettes:  Participants will be instructed to smoke their usual brand of cigarettes for the next 
week.  
Visit 2 [Day 8, + 3 days]
•
Review of participants continued compliance and eligibility.
•
The study cigarette log will be reviewed and the total number of cigarettes smoked each 
day will be recorded.
•
Participants will be given a 1 week supply of research cigarettes (150% of baseline 
cigarettes per day) that has a normal nicotine content (approx. 11 mg).  They will be 
instructed to smoke as they usually do.
•
Compliance with the study protocol including not using other forms of tobacco or 
marijuana will be stressed.  
•
Participants will be asked to honestly report any use of non-research cigarettes, other 
tobacco or marijuana at subsequent visits.  
•
Participants will be instructed to bring all cigarette packs (unopened, opened or empty) 
back to the study center at each study visit. Study staff will record the number of 
cigarette smoked and returned. Participants will be reminded that they will receive a final 
payment based on the accuracy of the packs they return.
Baseline II (2 weeks on usual nicotine content research (UNC) cigarettes)
The following procedures will be completed at each visit during Baseline II:
• Participants will be evaluated for continued compliance and eligibility for the study.
Anxiety symptoms 
questionnaire (ASQ)
X
X
X
X
X
CES-D
X
X
X
X
X
Kessler K6
X
X
X
X
X
X
X
X
X
X
X
OASIS (anxiety)
X
X
X
X
X
X
X
X
X
X
X
QIDS (depression)
X
X
X
X
X
X
X
X
X
X
X
Perceived stress scale
X
X
X
X
X
X
X
X
X
X
X
Clinical COPD questionnaire
X
X
X
X
X
X
X
X
X
X
Pittsburgh sleep symptom and 
Dreams questionnaires
X
Interheart and WI Prepare
X
Smoking Cessation (if chosen 
by participant)
X
X
X
NRT disbursement (if chosen by 
participant)
X
X
Biomeasures/Procedures¥
 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Waist hip ratio
X
X
 
X
Exhaled CO
X
X
X
x
X
X
X
X
X
X
X
X
Blood pressure/pulse
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function
X
X
X
X
X
X
X
X
Urine ( NNAL, 1-HOP, F2-Isoprostanes, 
Creatinine, )
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X
X
X
X
X
Blood (cotinine, GSH, GSSP, GSSP, 
Hemoglobin, DNA)
X
X
X
X
X
X
X
X
X
Payment
$40
$80
$40
$80
$80
$80
$80
$80
$80
$80
$80
$40+ 
comp
lianc
e
* To be completed by the researcher.  All others will be completed by the participant. ¥All biomeasures/procedures to be completed by 
researcher.   Some biomarkers will be analyzed in selected subgroups of collected samples.
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• Compliance with the study protocol including not using non-research cigarettes, other 
forms of tobacco or marijuana will be stressed.  
• Participants will be asked to rate their confidence in complying with the study protocol on a 
scale from 1-10, with 1 being no confidence and 10 being complete confidence.  Any 
scores < 6 will prompt the researcher to troubleshoot any challenges identified by the 
participant.
• Participants will be asked to honestly report any use of non-research cigarettes, other 
tobacco or marijuana. 
• Participants will be instructed to bring all cigarette packs (unopened, opened or empty) 
back to the study center at each study visit.  
Visit 3 [day 15]
Participants will be given a 1 week supply of research cigarettes (150% of baseline cigarettes 
per day) that approximately match the nicotine content of their usual brand of cigarettes.    
Visit 4 [day 22]
Participants who are eligible to continue to randomization will be given a choice to complete one 
of their weekly contacts via REDCap survey at home if they have a personal email address and 
reliable internet access.  
Participants will be given a 3 week supply of either UNC or RNC research cigarettes (150% of 
baseline cigarettes per day) corresponding to the participant’s treatment group allocation (see 
table in section 7.4.2).  
Randomized Double Blind phase (18 weeks on either UNC or gradually reduced nicotine 
content (RNC) cigarettes)
The following procedures will be conducted at each phone call or online survey during this 
phase:
Phone call or online survey [Day 29, 50, 71, 92, 113, 134]
Based on the participant’s choice at Visit 4, they will either receive a phone call or complete an 
online REDCap survey via an email link.  During this contact, they will complete the daily 
cigarette log and other tobacco use questionnaire, the Minnesota Withdrawal Scale and the 
Cigarette Liking Scale.  No personal information will be collected.  If the participant does not 
complete this contact, they will still be eligible to proceed in the study. However, every effort will 
be made to collect data retrospectively for any missed contacts at the next in person participant 
contact.
Payment:  $10
Phone call [Day 36, 57, 78, 99, 120, 141]
The main purpose of this contact is to remind the participant of their scheduled visit in 1 week 
and to collect daily cigarette log information.  If the participant does not complete this contact, 
they will still be eligible to proceed in the study however every effort should be made to collect 
data retrospectively for any missed contacts at the next in person participant contact.
Payment:  None
The following procedures will be followed for all in person visits during this phase:
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•
Participants will complete the questionnaires, biomeasures and procedures outlined in the 
“Randomized Double Blind Phase:  Measures, questionnaires and procedures” Refer to the 
time and events table.  
•
The study cigarette log will be reviewed and the total number of cigarettes smoked in the 
previous 6 days will be recorded (mean cigarettes per day will be imputed during statistical 
analysis for any missing days).  
•
A schedule of all study contact dates and times will be reviewed with the participant (online 
surveys, phone calls and in person visits). Any scheduling conflicts will be resolved and the 
participant provided with a new schedule of visits.
•
Participants will be asked to rate their confidence in complying with the study protocol on a 
scale from 1-10, with 1 being no confidence and 10 being complete confidence.  Any 
scores < 6 will prompt the researcher to troubleshoot any challenges identified by the 
participant.
•
Participants will be asked to honestly report any use of non-research cigarettes, other 
tobacco or marijuana at subsequent visits.  Compliance with the study protocol will be 
stressed.  
•
All cigarette packs from the previous weeks (unopened, opened or empty) will be collected 
by the researcher.
•
Participants will be reminded to bring all cigarette packs (unopened, opened or empty) back 
to the study center at each study visit
•
Participants will be given a 3 week supply of either UNC or RNC research cigarettes (150% 
of baseline cigarettes per day) corresponding to the participant’s treatment group allocation 
(see table in section 6.4.2).  
Study window for all randomization phase visits:  + 7 days (no study window for phone calls 
or surveys) when possible
Payment:  Participants will receive $80/visit ($20 for transportation, $20 for study visit 
completion and $40 for blood and urine) for every successfully completed study visit during the 
randomized phase 
 Visit 10 [Day 148]
Treatment Choice:
All participants will be encouraged to quit smoking and will be given information and resources 
to help smokers to quit (including the Surgeon General’s Report on “How Tobacco Causes 
Disease”).  Participants will then be given the choice to either 
1. Continue on the research cigarettes they have been using, for the next 12 weeks, 
2. Return to their usual brand of cigarettes, or 
3. Quit smoking with brief counseling from the study team and the option to use oral nicotine 
replacement (11 weeks of gum or lozenge).  Participants who choose to quit smoking will 
be offered a flexible treatment plan that includes optional extra contacts (2 in person and 
4 possible phone calls).  There will be no payments for the additional visits completed 
due to a participant choosing this option.  
Cigarettes:
• If participants choose to continue on research cigarettes, they will be given a 4 week supply 
of either UNC or RNC research cigarettes (150% of baseline cigarettes per day) 
corresponding to the cigarettes they were given in the last phase of the participant’s 
treatment group allocation (see table in section 7.4).  Participants will be instructed to bring 
all cigarette packs (unopened, opened or empty) back to the study center at their next visit.
• If participants choose to return to their usual brand of cigarettes, they will not be given any 
further research cigarettes.
• If participants choose to quit smoking they will be given up to a 6 day’s supply of research 
cigarettes corresponding to the cigarettes they were given in the last phase of the 
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participant’s treatment group allocation (see table in section 7.4). These cigarettes are 
intended to last until their target quit date  
Participants Who Choose to Make a Quit Attempt:   These participants will be offered a 
flexible smoking cessation treatment in which they will have the option to receive up to 11 
weeks of short acting nicotine replacement therapy (gum or lozenges) at no cost and 
cognitive behavioral based smoking cessation counseling provided by study staff either in 
person or over the phone. Participants interested in quitting smoking must be willing to set a 
quit date one day before the week 23 visit. These participants will be provided with up to a 6 
day’s supply of research cigarettes to use until their quit date.
By this visit, some participants will have transitioned to smoking very low nicotine content 
research cigarettes. In order to select an appropriate nicotine replacement (NRT) dose, 
participants will be asked to quit smoking the day before their next visit (week 23). 
Participants will be encouraged to call the state telephone quit line and/or use the Freedom 
from Smoking (FFS) quit website (http://www.ffsonline.org/) to supplement the brief, in-
person smoking cessation counseling sessions provided by study staff.
The following contact schedule will be provided to the participant:
Treatment Choice Phase (12 weeks of participant choice to return to usual brand, 
continue on research cigarettes, or quit smoking with help)
All Participants During Treatment Choice Phase:
The following procedures will be completed at study visit 11 and 12:
•
Participants will complete the questionnaires, biomeasures and procedures outlined in the 
“Treatment Choice Phase:  Measures, questionnaires and procedures” table below.  
•
The study cigarette log will be reviewed and the total number of cigarettes smoked will be 
recorded.  The participants will be given the opportunity to ask any questions they may 
have regarding keeping their log.  If needed, participants will be re-instructed on how to 
complete the log and will be given a supply of logs and small pencils.  
•
A schedule of the study contact dates and times will be reviewed with the participant (online 
surveys, phone calls and in person visits). Any scheduling conflicts will be resolved and the 
participant provided with a new schedule of visits. 
Schedule of contacts for participants who choose to quit smoking during the treatment choice phase
Wk22 
End 
rando
mized 
phase
-1d
Wk 
23
Day 
155
+1d
Wk 
24
Day 
162
Wk 
25
Day 
169
Wk 
26
Day 
176
Wk 
27
Day 
183
Wk 
28
Day 
190
Wk 
29
Day 
197
Wk 
30
Day 
204
Wk 
31
Day 
211
Wk 
32
Day 
218
Wk 
33
Day 
225
Wk 
34
Day
232
In Person 
counseling 
session
X
X
X
X
Telephone 
session
X
X
X
X
Self guided 
session
X
X
X
X
X
Quit day
X
Possible NRT 
disbursement
X
X
X
End of NRT 
use
X
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Cigarettes:
• Participants will be asked to honestly report any use of non-research cigarettes (for those 
who continued on research cigarettes), other tobacco or marijuana.  
• If participants chose to receive research cigarettes, all cigarette packs from the previous 
weeks (unopened, opened or empty) will be collected by the researcher.
• Participants will be instructed to bring all cigarette packs (unopened, opened or empty) 
back to the study center at their next visit.
• If participants choose to return to their usual brand of cigarettes, they will not be given any 
further research cigarettes.
• If participants choose to quit smoking they will not receive any research cigarettes even if 
they were not successful in quitting.  
Procedure for suicide risk at all visits where QIDS questionnaire is administered:  If 
participants indicate an answer of > 0 on item 12 of the QIDS questionnaire, the MINI Suicide 
module will be administered.  Scores of > 9 on the MINI Suicide module will require an 
assessment with a licensed clinician to document a clinical plan and a determination of 
retention or termination from the study.
Payment:  Participants will receive $80 ($20 for transportation, $20 for study visit completion 
and $40 for blood and urine).  
Study window for all Treatment Choice Phase visits (not including additional visits for 
those who are making a quit attempt): + 7 days when possible
Participants Who Choose to Make a Quit Attempt:   
Week 23 [Day 155]
At this visit participants will be evaluated by the researcher for nicotine withdrawal symptoms.  
If the participant chooses to use NRT they will receive 3 boxes of either nicotine gum (110 
pieces/box) or lozenges (81 pieces/box) (according to participant’s preference).  At Hershey, 
NRT will be dispensed by the Penn State Investigational Drug Service (IDS). Adverse Events 
and concomitant medications will be assessed and a questionnaire (Smoking Cessation Quit 
Day) that includes the Minnesota Withdrawal Scale (MNWS) will be completed by the 
participant.  
Decisions about dosing will be determined based on participant reported 
withdrawal symptoms.  Participants who will have tapered to very low nicotine cigarettes should 
have minimal withdrawal symptoms and will require very low NRT dose.  A general guideline 
for NRT Dosing will be used to make recommendations to participants as follows:
•
Group 1: 
o Not able to remain abstinent or
o Reports a score of 2 or more on the MNWS items #1 and #4 (irritable/ angry and/or 
craving to smoke)
•
Group 2:
o Able to remain abstinent and
o Reported a score of 0 or 1 on MNWS items #1 and #4 or 
o had few slips 
2mg Oral NRT (gum or lozenge) dosing guidelines for participants 
based on withdrawal symptom group allocation
Group
Max. number of pieces/day
Duration
Wk 23
1
1 piece as needed, not more than 
1 every 1 hr or 16 in 24 hours
3 weeks
2
1 piece as needed, not more than 
1 every 4 hrs or 6 in 24 hours
3 weeks
Wk 26
1
1 piece as needed, not more than 
1 every 2 hrs or 12 in 24 hours
4 weeks
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2
1 piece as needed, not more than 
1 every 6 hrs or 4 in 24 hours
4 weeks
Wk 30
   1
1 piece as needed, not more than 
1 every 4 hrs or 6 in 24 hours
4 weeks
   2
1 piece as needed, not more than 
1 every 8 hrs or 3 in 24 hours
4 weeks
The day after this visit, the researcher will call the participant to assess whether the participant 
is experiencing any side effects consistent with high nicotine levels and assess reducing the 
dose of NRT.  As needed, additional courses of NRT will be given to the participant either at 
study visits or if the participant calls in to the study center to request additional NRT. At week 
26 and 30 the dosing schedule will be discussed with the participant (see “Schedule of 
Contacts for participants who choose to quit” table in section 7.2).
General visit, phone, and self-guided sessions:
In addition to regular study visits (weeks 26 and 34), there will be two additional in person 
sessions (weeks 23 and 30), four phone sessions (weeks 23, 24, 28, and 32) and five self-
guided sessions. In order to avoid missed phone visits, researcher and participant will attempt 
to agree on a standing appointment, day and time.  At each contact expired CO will be 
measured, adverse events and concomitant medications will be assessed and participants will 
complete questionnaires.  Participants will receive 20 minutes (or less) of standard individual 
cognitive behavioral therapy (CBT) based on the Freedom from Smoking (FFS) curriculum 
(http://www.ffsonline.org/), from the American Lung Association.  They will be given strategies 
to cope with triggers/urges to quit and when appropriate, the researcher will help the participant 
make a test call to the quitline and/or use the FFS website.  
Week 26 [Day 176]
If participants chose to receive research cigarettes, they will be given an additional 8 week 
supply of either UNC or RNC research cigarettes (150% of baseline cigarettes per day) 
corresponding to the cigarettes there were given in the last phase of the participant’s treatment 
group allocation (see table in section 7.4).  
Participants who chose to use NRT to quit smoking, could be given a refill of oral NRT (3 boxes 
of gum or lozenge) as deemed appropriate by the researcher according to the participant’s NRT 
usage and withdrawal symptoms.
Week 34 [Day 232]
Cigarettes and cessation counseling:  No further counseling, NRT or study cigarettes will be 
given to the participants.  
Payment:  In addition, those participants who are eligible for the compliance incentive 
payments for good study compliance will be informed.  There are two possible compliance 
incentive payments:
•
Study visit attendance ($50):  Participants will be eligible for this compliance incentive if 
they attended all study visits and provide data.
•
Cigarette pack return accuracy ($50):  Participants will be eligible for this study 
compliance incentive if they returned all research packs (opened and unopened) within a 
margin of 4 packs for 6/8 study visits where research cigarette return was required (visit 3. 4, 
5, 6, 7, 8, 9, and 10). 
7.3       Duration of Participation
Participants who complete all phases of the study will participate in the study for 33 weeks.
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7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
Description
Participants will be provided with research cigarettes that have a similar nicotine content to 
current commercially available cigarettes (11mg).  Menthol smokers will be provided with 
menthol research cigarettes if that is their preference.  The following table describes the dosing 
and schedule for all study participants including the reductions for those randomized to the 
intervention during the Double-Blind Phase.    
At visit 10 participants enter the Treatment Choice Phase of the study.  At this timepoint, 
participants are given a choice to go back to their own brand of cigarettes, to quit, or to continue 
receiving research cigarettes for an additional 3 months. If a participant is in the RNC arm and 
they choose to continue with the research cigarettes for 3 more months, these participants will 
receive the same dose of cigarettes they received during the previous 3 weeks. 
For those who are in the UNC group and choose to continue on the research cigarettes, they 
will receive either the same dose they received during the previous 3 weeks OR they will 
receive the Step 1 RNC cigarettes (see table below) depending on supply availability.
Phase:
Baseline 
I
Baseline II
Randomized Double-Blind Nicotine Reduction Phase
Treatment 
Choice 
Phase
Wks/Phase:
2
2
3
3
3
3
3
12
Cigarette 
type:
Own 
Brand 
Usual 
Nicotine 
Research 
Cigarettes
Reduced 
Nicotine 
Step 1 
Reduced 
Nicotine 
Step 2 
Reduced 
Nicotine 
Step 3 
Reduced 
Nicotine 
Step 4 
Reduced 
Nicotine 
Step 5  
Variable
Nicotine content (mg/cigarette)
regular:
RNC
menthol:
Around 
11mg3
11 
12.1 
7.8 
7.0 
3.2 
3.4
1.3
1.4
0.7
0.7
0.2
0.2
Variable
regular:
UNC
menthol:
Around 
11mg
11
12.1 
11
12.1 
11
12.1 
11
12.1
11
12.1 
11
12.1 
Variable
7.4.3
Method for Assigning Subject to Treatment Groups
Participants will be randomized to one of two experimental conditions based on a pre-
determined random number sequence generated by Dr. Liao (head of PS TCORS Data 
Management Core).  A Cigarette Management System (CMS) has been created by the Public 
Health Sciences Data Management team to manage assigning randomized, blinded cigarettes 
to participants and to track cigarette inventory.  This system will store the randomization code. 
Randomization will be stratified by site (Penn State and Mass. General/Harvard) and by menthol 
flavor (regular/menthol). This ensures a similar distribution of treatment assignment (1:1 for 
gradual reduction: control) across study sites to avoid potential confounding.
7.4.4
Subject Compliance Monitoring
Participants will be given a daily log to complete on which they will tally the number of cigarettes 
they smoke each day.  Participants will be given detailed instructions on how to complete the 
log 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 and blood will be 
taken throughout the trial to verify smoking intensity, nicotine and cotinine levels.
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7.4.5
Blinding of the Test Article
Cigarette cartons will arrive in the IDS with a packaging slip that provides information about the 
cartons in the shipment which includes the nicotine content, carton bar code number and a 
batch/lot number.  This information will be carefully recorded by the Cigarette Manager in our 
CMS (Cigarette Management System), removed from the carton and replaced with a blind code 
number.  Individual packs do not contain any identifiable information.  Each individual pack will 
be labeled with the carton blind code.    
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.    
7.4.6.2 Storage
At Penn State Hershey, cigarettes will be stored in locked, -20 freezers that are maintained by the 
IDS.  Standard pharmacy 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.  At Harvard/Mass General, cigarettes will be stored at room temperature in locked 
cabinets in a locked office space.  At both sites, menthol cigarettes will be stored separately from 
regular cigarettes.
7.4.6.3 Preparation and Dispensing
Assignment:  When a new participant is entered into the CMS and is at the study visit where they 
receive cigarettes, the Cigarette Manager will enter the Participant ID, baseline cigarettes per day, 
and flavor preference into the CMS.  The CMS will provide the Cigarette Manager with the Blind 
Code numbers for the appropriate cartons of cigarettes (e.g., the correct cigarettes/nicotine level for 
the corresponding stage for where the participant is in the study).  
Preparation:  Once the cigarettes are received, they will be blinded by the Cigarette Manager 
under the supervision of the IDS.  At the time of dispensation, the CMS will instruct the Cigarette 
Manager which blind codes should be dispensed to the participant and the Cigarette manager will 
pull the correct cartons from the cigarette inventory.  The CMS will also tell the Cigarette Manager 
how many packs of cigarettes to dispense to the participant.  The cigarette manager will prepare a 
bag of cigarette packs that will be given to the study coordinator for the participant.  
Where:  All receiving, sorting, blinding of the initial study product will be done in IDS pharmacy 
space at Penn State Hershey.  Dispensing of product to study participants will also be done in the 
IDS pharmacy space at Penn State Hershey.  At Harvard/Mass General, cigarettes will be stored in 
locked cabinets in a locked research space and blinded cartons will prepared for dispensing in that 
space.
Dosing:  Dosing of cigarettes will follow the schedule outlined in section 7.4.
Dispensing:  Cigarette packs containing 20 cigarettes will be dispensed to the study coordinator 
during or 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, the 
blind code number, the flavor (regular or menthol) and a list of possible nicotine doses the 
cigarettes may contain. Packs will also be labeled with a color coded sticker that indicates the visit 
number at which they were dispensed. The coordinator will give the cigarettes to the participant at 
their visit.  The number of packs dispensed will be determined by the self-reported number of 
cigarettes per day they smoke when they enroll in the trial.  Participants will be provided with 150% 
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 at the next visit.  
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7.4.6.4 Return or Destruction of the Test Article
The CMS will track all receipt and dispensing of cigarettes for the duration of the project.  
Reconciliation reports will be produced on an ongoing basis.  
Participants will be instructed to return all research cigarette packs at the next visit, regardless of 
whether they are empty, unopened or partially used. Any unused experimental cigarettes that are 
returned from the participant will be destroyed by the IDS.  Harvard/Mass General will follow their 
site’s drug destruction policy.  We will not ship experimental cigarettes back to the NIDA Drug 
Supply Program or recycle opened cartons.
7.4.6.5 Prior and Concomitant Therapy
Concomitant medication use will be collected regularly throughout the trial to monitor participant 
health conditions.  
Participants taking varenicline, bupropion or nortriptyline as a smoking 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
Data and Specimen Banking
Blood and urine will be banked for future undetermined research.  Participants will be given an option 
on the consent form that will provide permission for the researchers to bank their specimens for future 
projects.  Only participants who consent to this option will have their specimens banked.
8.1
Data and/or specimens being stored 
Specimens will be stored with an ID code attached.  The location of the specimen in the study freezer 
will be managed using Freezerworks database which will be housed on the PHS password secured 
network.  The code number, visit number, date/time of collection, processing and storage, and consent 
options for future use of samples will be stored in Freezerworks in addition to REDCap.  All other data 
associated with the ID code will be retained in REDCap. 
8.2
Location of storage
Specimens will be stored a locked freezer room in the research laboratory of Drs. Muscat & Foulds on 
the 3rd floor of the Cancer Institute.  
8.3
Duration of storage
Specimens will be stored indefinitely with code number attached.  Data will be stored indefinitely with 
identifiers attached in REDCap and no identifiers in Freezerworks.
8.4
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, Harvard/Mass 
General coordinators will not have access to Penn State Hershey participant data, etc.).
8.5
Procedures to release data or specimens
Investigators who are interested in obtaining samples from this project for ancillary studies will first be 
required to submit a detailed written proposal to Dr. Foulds.  Dr. Foulds will then take the proposal to 
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the overall Penn State Tobacco Center of Regulatory Science (TCORS) steering committee for review 
and approval.  If the proposal is approved, the investigator will then need to obtain all other regulatory 
approvals (IRB, departmental scientific committees, etc.) prior to samples being released.  Only de-
identified data, as approved in the investigator’s IRB application, will be released to the investigator.  
Blood and urine samples will only be released if the participant provided written consent to allow their 
samples to be used by other investigators (this option is included in the original consent form).  
8.6
Process for returning results
Investigators will be required to provide a written report on their study results to the TCORS steering 
committee. Individual participants will not be provided with the results of the analyses of their samples.
9.0
Statistical Plan
9.1
Sample size determination
The primary outcome variable is plasma cotinine concentration (measured as ng/ml). The mean 
value of this continuous measurement will be compared between two groups: the experimental 
group (RNC cigarettes) and the control group (UNC cigarettes). For plausible effect size and 
variation, we use results of Benowitz et al (2012)(10), where the mean and standard deviation of 
plasma cotinine concentration are 240 and 120 for the control group and 113 and 116 for the 
experimental group at the 22nd week follow-up visit (end of randomization phase for trial). It is 
expected that the cotinine level in the experimental group will reduce gradually after start of the 
trial and the mean difference of the cotinine level between these two groups for our study will be 
smaller than the difference of 127 ng/ml in Benowitz et al (2012). With a sample size of 70 
participants per group, we are able to detect the difference in plasma cotinine concentration 
level between the two groups as small as 58 ng/ml (which could occur on the 8.6mg nicotine 
content cigarettes) with at least 80% power (and 68 ng/ml with at least 90% power). Allowing for 
a 30% participant -withdraw rate, we plan to recruit 100 participants for each group (a total of 
200). The alpha level used for the power analysis is 0.05.
Additional statistical power analyses were performed based on secondary hypotheses (e.g. 
hypothesis 1.b): to examine the difference in biomarkers of tobacco smoke exposure, nicotine 
withdrawal, and psychiatric symptomatology, with a sample size of 70 subject completers per 
group, we are powered to detect an effect size of 0.5 (difference is half of the standard 
deviation) between the two groups with at least 83% power. Also, with a completing sample size 
of 70 per group we are able to detect a 15 – 20% difference in the proportion of subjects  willing 
to quit between these two groups (depending on the proportion in the control group) with about 
80% power. If the proportion difference was as large as the value in the Benowitz et al (2012) 
study (51% of the RNC group versus 14% of the control group) then our statistical power will be 
as high as 99.8%. It was assumed that both groups have equal drop-out rate (30%) when the 
sample size was calculated above. However, it is possible that we could have differential drop-
out rate in the two groups. Benowitz et al (2012) had 9% dropout in the control group versus 
33% in the intervention group. We have 99% statistical power in detecting a difference as large 
as this.
9.2
Statistical methods
Preliminary Analyses:  Basic baseline statistics including means (SDs), medians (IQR), and 
frequency distributions (percentages) will be reported for demographic characteristics; smoking 
history and other baseline measures. Ranges for all variables will be obtained to identify 
possible outliers and coding errors. Where necessary, some characteristics will be reported by 
the two groups under investigation. 
Specific Analyses
Overall analytic plan:  Linear regression models will be  built  for each outcome variables of 
interest. The primary endpoint for these analyses will be the end of the randomized trial phase 
(Visit 10), while treating Visit 4 as the baseline. Unadjusted regression models will compare the 
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difference between the two trial arms while controlling for the baseline value of the outcome 
measure. Adjusted models will evaluate the randomized treatment effect while adjusting for the 
covariates that were selected via backward elimination using a significance level of 0.05. These 
models will be built on data from subjects who completed the randomized nicotine reduction 
phase (Visit 10).  We will conduct a separate statistical analysis for the subgroup of compliant 
participants.
Mixed effects regression models will also be used to study the change over the randomized 
nicotine reduction period of many longitudinal outcomes and to assess the difference of the 
trajectories between the randomized treatment arms. Models will be fit to evaluate the effects of 
time, group, and time-by-group interaction while adjusting for the baseline value (visit 4) for the 
corresponding outcome.
  The hypotheses to be tested are as follows:
Hypothesis 1.a.:  Smokers assigned to the RNC group will have lower plasma cotinine 
concentrations during the last 3 weeks (visit 10) of the randomized phase of the study than 
those assigned to the UNC group.
Hypothesis 1.b.:  There will be no significant increase in key markers of tobacco use (e.g. 
cigarette consumption), biomarkers of tobacco smoke exposure (e.g. NNAL, CO), or health 
effects (e.g. blood pressure) in those assigned to the RNC group vs. those assigned to UNC. 
Hypothesis 2: There will be no significant increase in ratings of psychiatric or nicotine 
withdrawal symptoms in those assigned to the RNC group as compared to those assigned to 
UNC.  
Hypothesis 3: Smokers assigned to the RNC group will have lower perceived dependence, be 
more likely to report intention to quit smoking at the end of the randomized trial phase, and be 
more likely to achieve cigarette abstinence at Visit 12.
Both ITT abstinence (based on the assumption that a loss-to-follow-up subject resumes 
smoking) and completers’ abstinence (based on the assumption that the probability of loss to 
follow up is independent of smoking status and abstinence can only be evaluated if the 
participant attended Visit 12) will be analyzed. Abstinence will be biochemically verified (CO < 
10ppm). 
A Kaplan-Meier survival analysis will be used to compare the time to dropout (from visit 4 date 
to date of dropping out  of the randomized nicotine reduction phase) between the two treatment 
groups.  Participants who completed the randomized nicotine reduction phase of the study (visit 
10) will be considered as censored records at the time of visit 10. The date of dropout prior to 
Visit 10 is defined as the last scheduled contact date that a subject provides meaningful 
research data. The time to dropout will be compared between the two trial arms. 
10.0 Confidentiality, Privacy and Data Management 
10.1
Confidentiality
The majority of study data at both sites will be collected and 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. 
REDCap is HIPAA compliant. Data are stored on a secure server at Hershey Medical Center 
and data in REDCap are encrypted.  Access to the database requires authentication (a unique 
username and password) and a user matrix will be used to ensure that only appropriate data 
are accessed based on the individual’s role on the project. Every interaction with the data is 
logged in REDCap creating an audit trail.  Some participants may elect to complete one contact 
per month via a REDCap survey link that will be sent to their personal email account.  No 
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personal information will be sent through email as these emails will only contain a link to the 
participant’s individual record in REDCap where they will be able to directly enter their 
information.
Paper files will be kept to a minimum and those that are generated will be stored in locked filing 
cabinets in the research offices of Dr. Jonathan Foulds.
Any electronic data generated (e.g. PFT reports) will be stored on the PHS computer network in 
password protected files.
10.1.1 Identifiers associated with data and/or specimens
The following personal identifiers will be collected:
• Name
• Address
• Phone numbers
• Email addresses
• Date of birth
• Social security number
10.1.1.1
Use of Codes, Master List
Study data will be collected in REDCap including a participant record 
number and a study specific code number.  The list connecting the 
participant data to the code numbers will be stored electronically in REDCap 
and will not be destroyed.  The PIs, Study Coordinators, Research 
assistants and Lab Managers will have access to the list.  
10.1.2 Storage of Data and/or Specimens
• Electronic data will be stored indefinitely in REDCap with identifiers attached. 
PFT reports will that are generated as a result of conducting the PFT test will be 
stored on the PHS computer network in password protected files. Data from 
these documents will be transferred into REDCap from the electronic file.
• Paper records:
o Paper will be stored at the site where they are acquired for the length of 
the study in locked filing cabinets.  Paper records will be scanned and 
uploaded into participant records in REDCap. Paper will be retained until 
the end of the study after which it will be destroyed.  Electronic copies will 
be stored indefinitely as above.
• Specimens:
o Specimens will be stored indefinitely with a code number attached. 
o Prior to processing, samples will be placed in a refrigerator by the study 
nurse, research assistant or study coordinator in the Clinical Research 
Center or in the key-card secured lab of Dr. Josh Muscat.
o Within 24 hours, samples will be processed by a lab manager and will 
then be secured in a freezer located in a locked room within the research 
laboratory of Dr. Josh Muscat on the 3rd floor of the Cancer Institute.
10.1.3 Access to Data and/or Specimens
Study data in REDCap:  Primary study personnel including: Primary Investigators, 
Study Coordinators, Research Assistants, and Lab Managers will have access to the 
REDCap data.  However, a REDCap user matrix will limit access to data based on the 
researcher’s role in the study. These researchers will also have access to electronic 
data stored on the PHS files.
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Specimens:  Lab managers, technicians, researchers and the PIs will have access to 
the specimens once they have been processed and secured in the locked laboratory 
freezer room.
10.1.4 Transferring Data and/or Specimens            
Processed, frozen specimens from the Harvard study site will be shipped via 
commercial carrier to Dr. Muscat’s Penn State laboratory for storage and analysis.  
10.2
Privacy
The research team will only have access to data that they have consented to provide and is 
provided by the participant during data collection contacts.  HIPPA guidelines will be followed for 
all participants.  Participants will be informed that they can refuse to answer any questions that 
make them feel uncomfortable.  The majority of personal data that the participants provide will 
be entered directly into REDCap by the participant.  All study visits, data collection and 
procedures will be completed in private consult rooms at the Penn State Hershey CTSI.
11.0  Data and Safety Monitoring Plan
11.1
Periodic evaluation of data
The study coordinator and the research nurse will be responsible for the daily oversight of 
subject safety.  Patients will be under medical supervision while in the study and seen on an 
ongoing basis by our research staff who will assess adverse events and make appropriate 
referrals to the physician.  Dr. Foulds and/or Dr. Hameed, will meet regularly with the study staff 
to review patient’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. Hameed or our nurse practitioner for any contraindications for the treatment 
products and vital signs will be checked at each in person visit. 
Similar procedures will be instituted at Harvard University under supervision of Dr. Evins.  Any 
adverse symptoms will be discussed over the telephone on our across site calls.  Drs. Foulds 
and Evins will conduct internal monitoring of subject safety across all sites. In addition, the Data 
and Safety Monitoring Board will oversee the safety of the participants in the trial. The DSMB 
will receive summary reports on recruitment, retention, AEs, and CO every 6 months and will 
meet and produce a report and recommendation at least annually.
11.2
Data that are reviewed 
Data that will be reviewed include:
•
Accrual and retention
•
Adverse events and serious adverse events
•
Protocol deviations/violations
•
Misconduct
•
Conflict of interest
•
Participants’ ability to achieve study requirements
•
Significant changes in mental health status including suicidal ideation
•
Changes in psychological measures of anxiety and depression (OASIS and QIDS)
•
Changes in cigarette consumption from baseline
•
Exhaled carbon monoxide increase from baseline
11.3
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.
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11.4
Frequency of data collection
Safety data including adverse events, serious adverse events and mental health assessments 
and carbon monoxide will be collected at each in-person visits.  Cigarettes smoked per day will 
be collected regularly either at in person visits, over the phone or via online REDCap surveys.
11.5
Individual’s reviewing the data
The study coordinator and the research nurse will be responsible for the daily oversight of 
subject safety.  Dr. Foulds and/or Dr. Hameed, will meet regularly with the study staff to review 
patient’s progress and their experiences with the tobacco products, including any adverse 
events.  Similar procedures will be instituted at Harvard/Mass General under supervision of Dr. 
Evins and Dr. Foulds.  
11.6
Frequency of review of cumulative data
Safety data will be reviewed cumulatively based on recommendations from the DSMB.  They 
will receive summary reports every six months and convene at least annually.
11.7
Statistical tests
Basic descriptive statistical methods will be used to analyze the safety data to determine 
whether harms are occurring. Changes in cigarette consumption from the baseline will be 
calculated. The exhaled carbon monoxide increase from baseline will be examined in the same 
way. In addition, the accrual and retention-dropout rate, completion rate, and the proportions of 
adverse events and serious adverse events will be generated. The data provided to the DSMB 
will not be separated by treatment group and will remain blinded. However, if the DSMB 
perceives a need to assess safety based on an unblinded analysis, they can request this 
information and it will be provided.
11.8
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 DSMB identify any issues after reviewing the data, they can 
develop stopping rules for the trial these recommendations will be followed.
12.0  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 or reduce their cigarette consumption will be 
recruited to the study. All participants will be free to reduce or quit smoking throughout the study, and 
smoking cessation treatment will be offered to all participants at the end of the randomized phase. 
Subjects will be under supervision throughout their participation in the study and adverse symptoms will 
be recorded at each in person clinic visit and monitored by the Project Leaders.   The major side effects 
associated with RNC cigarettes are similar to usual brand cigarettes.  
Additional potential risks include:
•
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 and exhaled carbon 
monoxide will be monitored throughout the trial.  Safety rules are in place to identify and remove 
participants to increase their smoking rate significantly (see section 3.3.1).
•
Nicotine withdrawal symptoms:  
Decreased nicotine cigarettes may result in nicotine 
withdrawal symptoms (e.g. irritability, anxiety, restlessness, depressed mood, increased 
appetite, fatigue, insomnia/sleep problems, impatience, headache, difficulty concentrating).  
These symptoms will be monitored regularly.
•
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.  For this reason women of child-bearing potential must agree to 
use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
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study entry and for the standard duration of the study.  Pregnancy status will be confirmed with 
a urinary pregnancy test every 4-8 weeks (see Time and Events Table).
•
Risks of standard venipuncture: The discomfort associated with removing blood by 
venipuncture (by needle from a vein) is a slight pinch or pin prick when the sterile needle enters 
the skin. The risks include mild discomfort and/or a black and blue mark at the site of puncture. 
Less common risks include a small blood clot, infection or bleeding at the puncture site, and on 
rare occasions fainting during the procedure. There will be only a small amount of blood drawn 
(about 2 teaspoons) every three weeks.
•
Spirometry:  Risks associated with lung function tests spirometry may include shortness of 
breath, dizziness or headache while doing the breathing test.  Participants with medical 
conditions that may place them at increased risk are being excluded.
•
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 questionnaires may make 
participants uncomfortable.  They will be instructed that they are free to skip any questions that 
make them uncomfortable.
•
Use of oral nicotine replacement:  During the Treatment Choice Phase of the study, 
participants will be encouraged to quit smoking and will be offered a 11 week supply of oral 
nicotine replacement therapy (NRT) (lozenge or gum).  NRT (lozenge or gum) is known to be 
safe and have only mild side effects.  For this reason they are generally sold over the counter.  
Excess nicotine can cause mild symptoms such as nausea, dizziness, diarrhea and rapid 
heartbeat.  Occasionally these (or other rarely occurring symptoms) are more severe.  There is 
a slight risk that subjects who have progressed to very low nicotine cigarettes and then choose 
treatment with the NRT will obtain more nicotine than they are used to.  A 24 hour period of 
cigarette and NRT abstinence will be recommended to the participants who want to quit.  
Participants will be seen after this waiting period and their craving and withdrawal will be 
assessed.  Those who have very low or no withdrawal or craving will be offered the lowest dose 
and frequency of NRT.  They may also choose to not use any NRT during their quit attempt.  
Those who elect to use NRT will be contacted regularly (see section 7.0 for study procedures 
during treatment choice phase) to monitor their tolerance.
The use of oral nicotine replacement allows the participant to self-monitor their urges and 
cravings and use only the amount of NRT that they feel is necessary.  A protocol to help the 
researcher determine the best dose of NRT to recommend to the participant will be used.  
Participants will be followed up within 48 hours of starting NRT to assess tolerance. 
13.0 Potential Benefits to Subjects and Others
13.1
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. Participants will receive 
financial compensation for their time and inconvenience.  Those who complete the study will be 
offered help to quit smoking including evidence based cessation treatment with nicotine 
replacement therapy and counseling.
13.2
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.
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This study is not designed to diagnose any disease or condition.  However, if during the course of 
conducting clinical procedures (e.g., blood pressure, lung function), 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 (blood pressure, lung function).  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.
At the end of the study, after all participants have completed the protocol, the investigators will send via 
email (if possible) or U.S. mail (if we do not have an email) all participants who completed the 
randomization visit (visit 4), a letter that lets them know to which study group they were randomized 
(see letter in study materials).
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  Number of Subjects
A total of 280 participants will be enrolled in the study at two sites with the aim of randomizing 200 who 
complete the baseline phase.  100 participants will be enrolled in the randomized phase at Penn State 
Hershey.  Participants will be started on the study protocol during Baseline I and Baseline II but will be 
removed from the study if they are not able to comply with the protocol.  We expect that approximately 
40 participants at each site drop out from the study prior to randomization (due to inability to comply 
with study protocol).
17.0  Resources Available
17.1 
Facilities and locations
All participant visits at Hershey will take place in the Penn State Hershey Clinical Research 
Center.
17.2
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.  Our 
recruitment strategy is designed to broadly disseminate information about the study to members 
of the community, and so we anticipate being able to recruit 140 over 3 years. 
17.3
PI Time devoted to conducting the research
Dr. Foulds has no clinical responsibilities and so the majority of his time is devoted to research, 
including this project. He is funded at 20% time for this study, and for additional time as co-PI of 
the overall Penn State Tobacco Center of Regulatory Science. The rest of the research team 
also have appropriate percent times covered by this grant.
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17.4
Availability of medical or psychological resources
All of our participants will be seen by appropriately trained research staff or a Licensed Nurse 
Practitioner. Any serious AEs or concerning test results will be passed on to participants along 
with a letter to their doctor. Our protocol for assessing suicide risk requires the availability of a 
licensed psychiatrist to evaluate participants if they indicate any score on the MINI suicide > 9 at 
screening or follow-up.  Any score on the QIDS questionnaire > 0 will trigger the study staff to 
complete the MINI Suicide module.  Scores > 9 on the MINI will trigger a psychiatric 
assessment. Any urgent health problem will require accompanying the participant to the ER, 
which is located in the same building.
17.5
Process for informing Study Team
At least monthly team meetings will be conducted at PSU and Harvard/Mass General where 
study procedures, questions and issues will be discussed and resolved.  In addition regular 
TCORS meetings will be held to discuss study progress.  Offsite locations will have the ability to 
call in to these meetings.
18.0 Other Approvals
An Investigational Tobacco Product (ITP) application has been submitted to and approved by the FDA. 
A Certificate of Confidentiality has also been obtained.  
19.0 Subject Stipend and/or Travel Reimbursements
Subjects will receive a $20 gift card per clinic visit to cover transportation costs for the 12 clinic visits 
($240).  In checks, subjects will receive $20 for completing each of the 12 clinic visits ($240), $10 for 
completing 6 survey or phone contacts ($60), and an additional $40 for the 9 visits when blood and 
urine samples are collected ($360).  At the end of the study, participants will receive $50 complying with 
the cigarette pack protocol (accurate returned packs within 4 packs for 6/8 visits) and $50 if they attend 
all study visits (compliance incentive). The total payment for a subject who completes all study 
procedures will be $1,000.  All payments will be made by check at Harvard/Mass General.  Payments 
at each visit will be made according to the following schedule:
Study Visit #
Transportation
Visit 
Completion
Blood/urine 
collection
Compliance 
incentive 
(attendance/ 
pack return)
Individual
Visit 
Total
Overall
Total
1, 3 and 12
$20
$20
$40
$120
Survey or 
phone call (6 
total)
$10
$10
$60
2, 4, 5, 6, 7, 
8, 9, 10, 11
$20
$20
$40
$80
$720
12
$50/50
$100
$100
Study total
$1,000
20.0 Multi-Site Research
20.1
Communication Plans
The study team at both sites will meet at least monthly over the phone for the length of the trial 
to review study standard operating procedures, discuss challenges, accrual, AEs, resolve 
unique participant issues that occur during study visits and ensure compliance with the study 
protocol. The Hershey PI will participate in a site visit at Mass General prior to the start of the 
trial. The PI or other designated representatives will conduct periodic audits on at least an 
annual basis thereafter. 
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20.2
Data Submission and Security Plan
The majority of study data will be directly coded into REDCap either by the research staff or at 
the participant’s clinic visit.  As a result, data security is embedded in the data collection plan.  
Paper copies of written consent will be periodically scanned and uploaded into the participant 
record in REDCap.  Harvard/Mass General will retain their consents on paper and will not 
upload them into the REDCap project but they will be made available for periodic audits.  Site 
audits will be conducted to ensure that paper data is secure.  Electronic data checks will be 
conducted to ensure that electronic data is being entered correctly.
20.3
Subject Enrollment
Screening and enrollment data will be directly coded into REDCap.  Randomization will take 
place through the Cigarette Management System (CMS) which will be a web-based system 
available to the study sites (but the blind code will only be known to the Investigational Drug 
Service staff at Hershey, and the Data Management Core).
20.4
Reporting of Adverse Events and New Information
All Adverse Event information (including serious AEs) will be coded directly into REDCap and 
will be monitored at each study site and by Drs. Foulds, Hameed and/or Evins on at least a 
monthly basis.  Adverse events will be recorded directly into REDCap at each in-person 
participant visit.  A summary report including analysis of AEs will be produced for the DSMB 
every 6 months and provided to the site PIs (without group breakdown), but only the DSMB will 
have the ability to examine patterns of AEs by group and to request an unblinded analysis if 
there is any cause for concern that needs to be clarified by an unblinded analysis.
20.5
Audit and Monitoring Plans
The study team will meet at least monthly over the phone to discuss any issues that might arise 
with participants, screening, enrollment, and participant adherence to the study protocol or 
problems with implementing the protocol at each site.  Data will be monitored through electronic 
data checks that will be executed in REDCap. The Penn State TCORS Data Management Core 
will conduct monthly data quality checks (missing data, data consistency across the same 
variable in different questions) and will inform the PIs at both sites of any irregularities that are 
detected.
21.0 Adverse Event Reporting 
21.1
Adverse Event Definitions
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 
suspected 
adverse reaction
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 
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 
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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.
21.2
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:
•
The test finding is accompanied by clinical symptoms
•
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.  
•
The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study
•
The test finding is considered an adverse event by the investigator.
21.3
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.
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.
21.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
21.4.1 Written IND Safety Reports
N/A
21.4.2
Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse 
Reactions
N/A
21.5
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 
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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. All product related adverse events of a non-serious nature will be reported to the 
IRB at the time of renewal.  
Any reportable adverse events that occur at Harvard/Mass General will first be reported to their 
IRB.  The subsequent IRB determination report from Harvard/Mass General will then be 
submitted to the Penn State Hershey IRB.
All serious adverse events that occur at either site (regardless of causality) will be submitted to 
the FDA within 5 business days.
The Data and Safety Monitoring Board will review all serious adverse events and provide 
recommendations. We will inform NIH and FDA of any significant action taken as a result of the 
Data and Safety Monitoring Board’s findings. We will inform the subjects of any changes in risk.
21.6
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 DSMB will begin by reviewing 
the protocol and establishing guidelines for data and safety monitoring including any additional 
procedures for unblinding of participants.  
21.7
Stopping Rules
The DSMB 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 
from each of these meetings for the study record and forwarded to the each of the study site’s 
Institute’s Institutional Review Boards (IRB).
22.0 Study Monitoring, Auditing and Inspecting
22.1
Study Monitoring Plan
22.1.1 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 (i.e., initial electronic 
PFT test reports), will be stored electronically on the PHS 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 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 
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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 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 at both sites are 
being executed in compliance with the protocol, and IRB policies.  
22.1.2 Safety Monitoring
The DSMB 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, sponsor and/or DSMB of all 
applicable AEs as appropriate. All final assessments of AEs will be made by a licensed 
medical professional who is an investigator on the research. 
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, FDA, and/or DSMB of all Unanticipated Problems/SAE’s.
22.2
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the Penn State 
quality assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).
23.0
References
1.
U. S. Department of Health and Human Services, How tobacco smoke causes disease: The biology 
and behavioral basis for smoking-attributable disease: A Report of the Surgeon General, 2010, Public 
Health Service, Office of Surgeon General: Rockville, MD.
2.
U. S. Department of Health Human Services, The Benefits of Smoking Cessation1990, Washington, 
DC: Public Health Service, Centers for Disease Control Center for Chronic Disease Prevention and 
Health Promotion, Office on Smoking and Health.
3.
Connolly, G.N., et al., Trends in nicotine yield in smoke and its relationship with design characteristics 
among popular US cigarette brands, 1997-2005. Tob Control, 2007. 16(5): p. e5.
4.
O'Connor, R.J., et al., How do different cigarette design features influence the standard tar yields of 
popular cigarette brands sold in different countries? Tob Control, 2008. 17 Suppl 1: p. i1-5.
5.
Kozlowski, L.T., et al., Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the 
United Kingdom, and the United States. Tob Control, 1998. 7(4): p. 369-75.
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6.
U. S. Congress, Family Smoking Prevention and Tobacco Control Act., HR 1256, 2009, U. S. 
Government Printing Office: Washington, DC.
7.
Henningfield, J., et al., Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American 
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8.
Hatsukami, D., et al., Reduced nicotine content cigarettes: effects on toxicant exposure, dependence 
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9.
Benowitz, N.L., et al., Nicotine and carcinogen exposure with smoking of progressively reduced nicotine 
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10.
Benowitz, N.L., et al., Smoking behavior and exposure to tobacco toxicants during 6 months of smoking 
progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev, 2012. 21(5): p. 
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11.
Benowitz, N.L., P. Jacob, 3rd, and B. Herrera, Nicotine intake and dose response when smoking 
reduced-nicotine content cigarettes. Clin Pharmacol Ther, 2006. 80(6): p. 703-14.
12.
Lasser, K., et al., Smoking and mental illness: A population-based prevalence study. JAMA, 2000. 
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13.
Weinberger, A.H., et al., The relationship of major depressive disorder and gender to changes in 
smoking for current and former smokers: longitudinal evaluation in the US population. Addiction, 2012. 
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14.
Breslau, N., M.M. Kilbey, and P. Andreski, Nicotine withdrawal symptoms and psychiatric disorders: 
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15.
Dedert, E.A., et al., Smoking withdrawal in smokers with and without posttraumatic stress disorder. 
Nicotine Tob Res, 2012. 14(3): p. 372-6.
16.
Strasser, A.A., et al., New lower nicotine cigarettes can produce compensatory smoking and increased 
carbon monoxide exposure. Drug Alcohol Depend, 2007. 86(2-3): p. 294-300.
17.
Harris, J.E., Incomplete compensation does not imply reduced harm: yields of 40 smoke toxicants per 
milligram nicotine in regular filter versus low-tar cigarettes in the 1999 Massachusetts Benchmark 
Study. Nicotine Tob Res, 2004. 6(5): p. 797-807.
18.
Aubin, H.J., et al., Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ, 2012. 345: p. 
e4439.
19.
Hatsukami, D., et al., Biomarkers to assess the utility of potential reduced exposure tobacco products. 
Nicotine Tob Res, 2006. 8(4): p. 599-622.
20.
Benowitz, N.L., et al., Progressive commercial cigarette yield reduction: biochemical exposure and 
behavioral assessment. Cancer Epidemiol Biomarkers Prev, 2009. 18(3): p. 876-83.
21.
Lawrence, D., F. Mitrou, and S.R. Zubrick, Smoking and mental illness: results from population surveys 
in Australia and the United States. BMC Public Health, 2009. 9: p. 285.
22.
Goodwin, R.D., M.J. Zvolensky, and K.M. Keyes, Nicotine dependence and mental disorders among 
adults in the USA: evaluating the role of the mode of administration. Psychol Med, 2008. 38(9): p. 1277-
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23.
Ziedonis, D., et al., Tobacco use and cessation in psychiatric disorders: National Institute of Mental 
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Piper, M.E., et al., Using decision tree analysis to identify risk factors for relapse to smoking. Subst Use 
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Piper, M.E., et al., Anxiety diagnoses in smokers seeking cessation treatment: relations with tobacco 
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26.
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release. Biol Psychiatry, 2009. 66(9): p. 898-901.
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