Effects of Random Nicotine Delivery on Smoking Cessation
Phase: PHASE1
Conditions: Smoking Cessation, Cigarette Smoking, Smoking (Tobacco) Addiction
Sponsor: Milton S. Hershey Medical Center

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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Effects of Random Nicotine Delivery on Smoking Cessation
Principal Investigator:
Patricia Sue Grigson, PhD
Neural and Behavioral Sciences
(717) 531-5772
psg6@psu.edu
Version Date:
5/6/2019
Clinicaltrials.gov Registration #:
NCT03674970
Table of Contents
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1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Confidentiality, Privacy and Data Management
10.0
Data and Safety Monitoring Plan
11.0
Risks
12.0
Potential Benefits to Subjects and Others
13.0
Sharing Results with Subjects
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
15.0
Economic Burden to Subjects
16.0
Resources Available
17.0
Other Approvals
18.0
Multi-Site Research
19.0
Adverse Event Reporting
20.0
Study Monitoring, Auditing and Inspecting
21.0
Future Undetermined Research: Data and Specimen Banking
22.0
References
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1.0
Objectives
1.1
Study Objectives
The objective of this study is to determine whether treatment with random nicotine delivery via nicotine 
film both before and after the quit date will facilitate cessation relative to treatment with steady state 
delivery or placebo. We hypothesize that smoking cessation will be greater in subjects assigned to a 
random nicotine delivery regimen (as compared to those assigned to a steady state or placebo regimen). 
The nicotine film product is not part of the standard of care and is not available in non-investigational 
settings in the United States.
1.2
Primary Study Endpoints
The primary endpoints for the study include the percent reduction in the number of cigarettes smoked 
and the accompanying percent reduction in exhaled carbon monoxide (CO) levels.
1.3
Secondary Study Endpoints
The secondary endpoints include subjective ratings of the films and side effects.
2.0
Background
2.1
Scientific Background and Gaps
According to the CDC, cigarette smoking is associated with profound morbidity and mortality. In the 
United States alone, cigarette smoking is responsible for about 480,000 deaths per year1 and costs the 
nation more than $300 billion annually.2 About 15% of all adults smoke in the United States and by 12th 
grade, 42% of students report having smoked. Starting, however, is one problem and stopping is 
another. Cigarette smoking is a disease of chronic relapse. Indeed, once having started, smokers will 
make as many as 20 quit attempts before they are successful3 and abstinence rates can be as low as 7%, 
even following NRT with the patch, gum, or nasal spray.4 As with other addictions, cue-induced craving 
contributes to relapse following a quit attempt.5
From a global perspective, it would seem that there are three options for the treatment of cigarette 
smoking: no support (unaided cessation), behavioral support of one manner or another, and/or 
pharmacological intervention. With nearly 70% of smokers reporting that they would like to quit, yet 
most failing, we must assume that will, alone, is not sufficient. Certainly, the ability to quit any addiction 
can be bolstered by behavioral and/or pharmacological support. Contingency management is a 
behavioral intervention where abstinence is reinforced with tangible incentives such as money. 
However, individuals addicted to smoking may be insensitive to the very reward upon which their 
behavior is contingent.6,7 NRT is a long-standing and widely used smoking cessation tool. Yet, as 
discussed, NRT too is only modestly effective. We propose that the limited effectiveness of NRT is due, 
at least in part, to a failure to prevent cue-induced craving and relapse. In support, NRT treatment does 
not attenuate stimulus-elicited drug seeking.  Here we propose a novel alternative to the steady-state 
delivery of nicotine (i.e., to the standard patch) for the treatment of smoking cessation. Specifically, we 
propose to use an oral film to treat smokers wishing to quit with random, rather than steady-state, 
delivery of nicotine prior to and following the quit date.
2.2
Previous Data
Support for our random delivery hypothesis is provided by both preclinical and clinical data suggesting 
that yoked (i.e., uncontrollable/unpredictable) delivery of drug impairs the development of cue-drug 
associations, retards or disrupts responding for drug or alcohol, and can even render the drug aversive. 
In rats, yoked delivery of ethanol retarded later acquisition of ethanol self-administration8 and, in our 
hands, a history of yoked delivery of cocaine9 disrupted the willingness to work for the drug on a 
progressive ratio schedule of reinforcement. Although fixed ratio (FR) responding appears normal in rats 
with a history of yoked delivery of cocaine, the averaged data occlude the fact that rats yoked to high 
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drug-takers actually took only about 4 infusions/hour on the FR schedule. To be effective, however, 
yoked delivery of drug needs not only delay acquisition in drug inexperienced rats, but must effectively 
rescue subjects with a strong drug habit. In accordance, Twining and Mueller (in preparation) found that 
yoked delivery of cocaine rescued cocaine-experienced rats by reducing drug seeking during extinction 
and by reducing drug-taking during subsequent FR testing. In humans, Donny et al10 reported that yoked 
delivery of cocaine led to an increase in mean systolic and diastolic blood pressure in response to the 
drug because of a lack of cue-supported tolerance. Scheduled availability of ethanol led to a marked 
decrease in intake of ethanol in a controlled setting.11  Finally, a meta-analysis showed that pre-
cessation treatment with a standard (i.e., steady state) nicotine patch doubled the odds of quitting 
smoking relative to subjects that received only post-cessation treatment with the nicotine patch.12-14  
Rose and Behm, too, found abstinence enhanced by pre-cessation treatment with the nicotine patch.15 
Foulds reported that use of the nicotine patch while smoking led to a 14% reduction in expired carbon 
monoxide (CO), reduced satisfaction from smoking, and fewer and weaker reported urges to smoke.16  
These marked effects are thought to be due, at least in part, to separation of blood nicotine levels from 
the act of smoking.15  Dissociation of smoking behavior and cues from nicotine is expected to be even 
greater with random nicotine delivery.
2.3
Study Rationale
There is, as yet, no ‘random patch’. Random delivery via a subcutaneously placed chip or pump is 
conceivable, but would be invasive and expensive. Here we propose to test the merits of our hypothesis 
simply by using a trans-mucosal nicotine orally dissolving film that has been tested and is safe for use in 
humans.17,18 In a pharmacokinetics study, we found that plasma nicotine levels achieved by the nicotine 
film are similar to those resulting from consumption of equivalent doses of other oral NRT products.19 
The films were well-tolerated in this study and produced mild side effects that were similar in nature to 
those of currently available NRT.19 The film is easy to use and tastes pleasant to humans. No water is 
required, as the film simply adheres to the roof of the mouth until dissolved (less than 5 minutes). 
Indeed, unlike nicotine gum, there are no complicated instructions regarding how and when to chew. 
The film can be used to deliver any dose of nicotine desired over time and placebo films are readily 
available. Finally, if the hypothesis proves correct, this novel treatment should be fairly inexpensive and 
available over the counter. As such, it will be both accessible and affordable, even for low-income 
smokers.
 
If this ‘random film’ were to work as predicted, cigarette cues would be dissociated from the act of 
smoking, smokers maintained on the random film would be more likely to achieve cessation. This would 
be a remarkable advance for the treatment of smoking and would inform the treatment of other 
addictions as well.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1.
Aged 18-55
2.
Smoke ≥10 cigarettes/day for at least the past 12 months
3.
Exhaled CO measurement ≥6 ppm at baseline visit
4.
Interested in completely ceasing cigarette consumption and using a nicotine film product as directed 
5.
Willing to attend regular visits over a 6-week period (not planning to move, not planning extended 
vacation, no planned surgeries)
6.
Able to read and write in English 
7.
Able to understand and consent to study procedures
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3.2
Exclusion Criteria
1.
Unstable or significant medical conditions and conditions such as elevated blood pressure (systolic 
>159 mmHg or diastolic >99mmHg at baseline), COPD, and those conditions that are likely to affect 
participant safety such as kidney or liver disease
2.
Individuals with sodium-restricted diet, heart disease, recent heart attack, irregular heartbeat, 
stomach ulcers, or diabetes as well as those taking prescription medications for depression or 
asthma as indicated under “Warnings” section on FDA approved NRT Drug Facts Label
3.
More than weekly use in the past 3 months of illegal drugs or prescription drugs that are not being 
used for medically prescribed purposes
4.
Use of non-cigarette nicotine delivery product in the prior 7 days (including cigars, pipes, chew, 
snus, hookah, electronic cigarette and marijuana mixed with tobacco)
5.
Use of an FDA approved cessation medication in the past 7 days (any NRT, Chantix, Wellbutrin)
6.
Women who are pregnant (verified by urine pregnancy test at baseline visit), trying to become 
pregnant, or nursing
7.
Uncontrolled mental illness or substance abuse or inpatient treatment for these conditions in the 
past 6 months
8.
Any previous adverse reaction to NRT
9.
Any other condition, serious illness, or situation that would, in the investigator’s opinion, make it 
unlikely that the participant could comply with the study protocol
10. Other member of household currently participating in the study
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
The PI reserves the right to remove a participant from the study for any reason, based on their 
discretion in order to protect the safety of a participant. 
3.3.1.1 Withdrawal prior to randomization
Participants who meet any criteria below at Visit 2 will be considered for 
withdrawal prior to randomization:

Not smoking ≥10 cigarettes/day for at least 5 out of the past 7 days

Use of a non-cigarette nicotine delivery product in the past 7 days

Reporting a quit attempt in the past 30 days
3.3.1.2 General withdrawal criteria
Participants may be discontinued by the PI at any point during the study for any of 
the following reasons: 

Missing their study visit window: If a participant misses their study visit 
window, the participant will be considered for withdrawal from the study.

New pregnancy: Participants who report a new pregnancy at any point 
during the study will be withdrawn.

Cardiovascular disease (CVD) event requiring inpatient hospitalization: 
CVD typically includes MI (heart attack), PTCA (angioplasty/stenting), 
bypass surgery, stroke, peripheral vascular disease (arterial blockages in 
arms or legs leading to procedure or surgery). Less common CVD problems 
would be new cardiac arrhythmias (e.g., new atrial fibrillation) or new 
vavlular disease (e.g., mitral or aortic regurgitation).

DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in 
the venous system) requiring inpatient hospitalization.

Adverse events related to nicotine film use: Adverse events, including 
symptoms of nicotine overdose (nausea, vomiting, dizziness, weakness, or 
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rapid heartbeat) or allergic reactions to the nicotine film, will be monitored 
at every study visit.

Worsening substance abuse in which the participant is behaving 
inappropriately at visits or demonstrates an inability to continue with the 
study.

Any inpatient hospitalization or debilitation in which participation in the 
study could be detrimental to the recovery process. This will be self-
reported by the participant and will be reviewed by the site PI and medical 
professional to determine whether continued participation in the study is 
appropriate (this could include recovery from a major surgery, worsening 
of psychiatric symptoms, etc.).

Any situation where participant is not able to use their study product for 
a period of more than 2 weeks (e.g., incarceration or other similar 
situation) unless they report non-study product use by choice.

Participant choice: Participants may choose to remove themselves from 
the study by informing the research team in writing at any point during the 
study. If they choose to remove themselves from the study, they will not 
receive any further contact from the study center.

Participant behavior: If a participant is behaving in an inappropriate or 
threatening manner, admits to lying about eligibility criteria, is 
participating in other smoking research studies that could affect the 
primary outcome measures, appears/admits to giving away/selling study 
products, consistently loses study products, etc., then the PI can withdraw 
him/her from the study at the PI’s discretion.
3.3.2
Follow-up for withdrawn subjects
If participants are withdrawn from the study for any of the reasons noted above prior to 
randomization, they will be replaced until a total of 45 participants have been randomized to 
the study. Reasons for withdrawal will be ascertained from subjects who voluntarily withdraw 
from the study (See End of Trial Form).
4.0
Recruitment Methods
4.1
Identification of subjects
All recruitment for this study will be routed through IRB STUDY00002213 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 STUDY00002213. If a participant’s responses match this study’s specified inclusion 
criteria they will be forwarded to research staff for further screening.
4.3
Recruitment materials
See IRB STUDY00002213.
4.4
Eligibility/screening of subjects
1.
Screener 1 (Phone):  We will consider the screening process and eligibility questions in IRB 
STUDY00002213 as Screener 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.
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2.
Screener 2 (Phone):  A full script and screening questions specific to this study are in the “Consent 
Forms and Recruitment Materials” section of the IRB application.
3.
Screener 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 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 Clinical 
Research Center.
5.1.1.2 Coercion or Undue Influence during Consent
Once potential study volunteers are identified, they will be given information 
about the study and offered the opportunity to participate. The researchers 
obtaining consent will be instructed to clearly indicate that the participant’s 
enrolling in the trial is purely voluntary and the researchers will not offer 
comments about whether they believe the participant should enroll in the study 
or not. 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 written consent. The participant will be 
given a copy of the signed consent. The participant’s signed consent form will be uploaded into 
the participant’s REDCap record.
5.2.2
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
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 
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5.3.1
Non-English Speaking Subjects
N/A
5.3.2
Cognitively Impaired Adults
N/A
5.3.2.2 Capability of Providing Consent
N/A
5.3.2.3 Adults Unable To Consent
N/A
5.3.2.4 Assent of Adults Unable to Consent
N/A
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
N/A
5.3.3.2 Parental Permission
N/A
5.3.3.3 Assent of subjects who are not yet adults
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:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
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6.2.1.1 Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol.
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
All study data will be retained indefinitely. Paper records will be kept in a safe area 
in Dr. Grigson’s locked research office.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
The phone screener (Screener 2) will be used to check eligibility criteria (date of birth), and 
when participants are screened, their contact information will be used to follow-up about 
scheduling and for appointment reminders. This requires that we have complete contact (name, 
phone number) information.
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 screening 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 randomized, double-blind, placebo-controlled, parallel-group study that will occur in three 
phases over 7 weeks. 
Time & Events Table
Baseline
Pre-Cessation
Cessation
Study Week Number
-1
0
1
2
3
4
5
6
Study Visit Number 
1
2
Ph #1
3
Ph #2
4
Ph #3
5
Study Day Number
-7
0
7
14
21
28
35
42
 
MEASURES
Screener 3
X
Concomitant medications
X
X
X
X
X
X
X
X
Medical history
X
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NIDA Quick Screen
X
Cigarette details
X
Adverse events
X
X
X
X
X
X
X
Daily cigarette/film diary 
collection
X
X
X
X
X
X
X
Demographics
X
Tobacco Use History
X
Environmental Tobacco 
Smoke Questionnaire 
X
X
X
X
Cigarette Evaluation Scale
X
X
X
X
X
X
X
Nicotine dependence
X
X
X
X
Minnesota Withdrawal Scale
X
X
X
X
Questionnaire Smoking Urge
X
X
X
X
Perceived Stress
X
X
X
X
Confidence to quit
X
X
X
X
Study product side effects
X
X
X
X
X
X
Study product evaluation
X
X
X
X
X
X
Likelihood of Use Scale
X
X
X
Dose Awareness
X
BIOMEASURES
Height
X
Weight
X
X
X
X
Waist/Hip ratio
X
X
Exhaled CO
X
X
X
X
X
Blood pressure & pulse
X
X
X
X
X
Pregnancy test
X
X
X
7.2
Study Procedures
7.2.1
Baseline Phase – Visit 1 (Consent Visit, Day -7)
At the first study visit, the following procedures will be conducted:
7.2.1.1
Prior to informed consent procedures, participants will complete the same 
screening questions completed over the phone previously (via Screener 2) to 
confirm eligibility (Screener 3). If participant meets eligibility criteria assessed via 
Screener 3, they will continue with Visit 1 and be asked to provide informed 
consent.
7.2.1.2
Pregnancy exclusion will be confirmed through a urine test that will be self- 
administered by the participants when they come to this visit. Participants with 
confirmed pregnancy will be withdrawn from the study and the End of Trial form 
will be completed.
7.2.1.3
Medical history will be documented to ensure that the participant does not have 
any conditions that may make them ineligible for the study.
7.2.1.4
Concomitant medication history will be recorded to ensure that the participant is 
not taking any medications that may make them ineligible for the study.
7.2.1.5
Details of participants’ usual brand cigarettes, including brand name and other 
characteristics, such as flavor, will be recorded. 
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7.2.1.6
Exhaled CO ≥6 ppm will be confirmed. Participants with a CO reading lower than 6 
ppm will be withdrawn from the study and the End of Trial form will be 
completed.
7.2.1.7
The NIDA Quick Screen will be administered and participants indicating the use of 
prescription drugs for non-medical use, illicit drugs, and/or marijuana daily, 
almost daily, or weekly over the past 3 months will be withdrawn from the study 
and the End of Trial form will be completed.
7.2.1.8
Blood pressure and pulse will be measured. Participants with a blood pressure of 
systolic >159 mmHg or diastolic >99 mmHg will be withdrawn from the study and 
the End of Trial form will be completed.
7.2.1.9
Participants who meet all eligibility criteria will complete the measures indicated 
on the Time & Events Table for the baseline visit. Measures will be completed 
electronically on a participant computer via REDCap. Participants will be given a 
laptop with access only to the internet, and an individualized REDCap survey will 
be opened so they can complete direct data entry.
7.2.1.10 Participants will be instructed to continue smoking their usual brand of cigarettes 
for the next week, to avoid using any other tobacco products, and to maintain a 
daily diary of cigarette use on which they will record the number of cigarettes 
they smoke each day.
7.2.1.11 Participants will be compensated for completing the study visit and procedures.
7.2.2
Pre-Cessation Phase – Visit 2 [1 week after Visit 1] (Day 0 -1/+3 days)
7.2.2.1
Adverse events will be documented.
7.2.2.2
The cigarette daily diary will be reviewed and recorded by the researcher to 
confirm that the participant completed their diary, that ≥10 cigarettes were 
smoked on at least 5 out of the last 7 days, and that no quit attempts have been 
reported. If any of these criteria have not been fulfilled, the participant will be 
excluded from randomization, and the End of Trial Form will be completed.
7.2.2.3
Use of other tobacco products in the past 7 days will be assessed. If the 
participant has used any other tobacco product in the past 7 days, they will be 
excluded from randomization, and the End of Trial Form will be completed.
7.2.2.4
Concomitant medications will be assessed to confirm participants have not 
initiated nicotine replacement therapy or cessation medication use since Visit 1. If 
they have initiated either of these medication categories, they will be excluded 
from randomization, and the End of Trial Form will be completed.
7.2.2.5
Participants who meet all eligibility criteria for randomization will complete the 
measures and study procedures indicated on the Time & Events Table for the visit.
7.2.2.6
Following randomization, subjects will receive their assigned study products. 
Research staff will explain how to use the nicotine films and provide participants 
with administration and dosing instructions. Participants will receive a 14-day plus 
3-day supply of the assigned film regimen (68 films total). The films will be 
packaged and numbered so they are taken in a specific, sequential order 
throughout each day. Participants will be instructed to take one film every 3-4 
hours each day for a total of 4 films per day.
7.2.2.7
Participants will be asked to return all used (opened/empty) and unused 
(unopened) study product pouches at their next study visit.
7.2.2.8
Participants will be instructed to continue smoking their usual brand of cigarettes 
ad libitum over the next two weeks and to avoid using any other tobacco 
products.
7.2.2.9
Participants will be instructed to maintain a daily diary of both their cigarette use 
and nicotine film use. This diary will require that they record the number of 
cigarettes they smoke each day and the time of day each film was taken.
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7.2.2.10 Participants will be compensated for completing the study visit and procedures.
7.2.3
Pre-Cessation Phase – Phone Call #1 (Day 7 ± 3 days)
During this phone contact, daily cigarette/film diary information will be collected, adverse 
events and changes to concomitant medications will be documented, and participants will be 
asked to verbally answer the measures indicated in the Time and Events Table during the phone 
call. Participants’ answers will be entered directly into REDCap by the researcher at the time of 
the call.
7.2.4
Cessation Phase – Visit 3 (Day 14 ± 3 days)
At this in-person visit, the following procedures will be conducted: 
7.2.4.1
Adverse events will be documented, and any concomitant medication changes will 
be recorded.
7.2.4.2
The daily cigarette/film diary will be collected and recorded by the researcher. 
Use of other tobacco products in the past 7 days will also be assessed.
7.2.4.3
Participants will complete the measures and study procedures indicated in the 
Time & Events Table. 
7.2.4.4
All nicotine pouches from the previous weeks (unopened, opened, or empty) will 
be collected by the researcher.
7.2.4.5
Participants will be provided with a new supply of their assigned nicotine films 
(14-day plus 3-day supply [68 films total]) to use over the next two weeks until 
their next study visit. 
7.2.4.6
Participants will be asked to return all used (opened/empty) and unused 
(unopened) study product pouches at their next study visit.
7.2.4.7
Participants will be instructed to cease all cigarette use and to only use their 
assigned nicotine films beginning the next morning. 
7.2.4.8
Participants will be provided with the document from the Centers for Disease 
Control and Prevention titled, “A Report of the Surgeon General: How Tobacco 
Smoke Causes Disease.” Participants will also be given a document with tips to 
prepare and succeed in a quit attempt.
7.2.4.9
Participants will be instructed to continue to maintain a daily diary of their 
nicotine film use. This diary will require that they record the time of day each film 
was taken. Participants will be instructed to only record cigarettes smoked on 
their diary in the event that they experience a slip.
7.2.4.10 Participants will be compensated for completing the study visit and procedures.
7.2.5
Cessation Phase – Phone Call #2 (Day 21 ± 3 days)
During this phone contact, daily nicotine cigarette/film diary information will be collected, 
adverse events or changes to concomitant medications will be documented, and participants 
will be asked to verbally answer the measures indicated in the Time and Events Table during the 
phone call. Participants’ answers will be entered directly into REDCap by the researcher at the 
time of the call.
7.2.6
Cessation Phase – Visit 4 (Day 28 ± 3 days)
At this in-person visit, the following procedures will be conducted: 
7.2.6.1
Adverse events will be documented, and any concomitant medication changes will 
be recorded.
7.2.6.2
The daily cigarette/film diary will be collected and recorded by the researcher. 
Use of other tobacco products in the past 7 days will also be assessed.
7.2.6.3
Participants will complete the measures and study procedures indicated in the 
Time & Events Table. 
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7.2.6.4
All nicotine pouches from the previous weeks (unopened, opened, or empty) will 
be collected by the researcher
7.2.6.5
Participants will be provided with a new supply of their assigned nicotine films 
(14-day plus 3-day supply [68 films total]) to use over the next two weeks until 
their next study visit. 
7.2.6.6
Participants will be asked to return all used (opened/empty) and unused 
(unopened) study product pouches at their next study visit.
7.2.6.7
Participants will be encouraged to remain abstinent from cigarettes.
7.2.6.8
Participants will be instructed to continue to maintain a daily diary of their 
nicotine film use. This diary will require that they record the time of day each film 
was taken. Participants will be instructed to only record cigarettes smoked on 
their diary in the event that they experience a slip.
7.2.6.9
Participants will be compensated for completing the study visit and procedures.
7.2.7
Cessation Phase – Phone Call #3 (Day 35 ± 3 days)
During this phone contact, daily cigarette/film diary information will be collected, adverse 
events or changes to concomitant medications will be documented, and participants will be 
asked to verbally answer the measures indicated in the Time and Events Table during the phone 
call. Participants’ answers will be entered directly into REDCap by the researcher at the time of 
the call.
7.2.8
Cessation Phase – Visit 5 (Day 42 ± 3 days)
At this in-person visit, the following procedures will be conducted: 
7.2.8.1
Adverse events will be documented, and any concomitant medication changes will 
be recorded.
7.2.8.2
The daily cigarette/film diary will be collected and recorded by the researcher. 
Use of other tobacco products in the past 7 days will also be assessed.
7.2.8.3
Participants will complete the measures and study procedures indicated in the 
Time & Events Table. 
7.2.8.4
All nicotine pouches from the previous weeks (unopened, opened, or empty) will 
be collected by the researcher
7.2.8.5
Participants will be encouraged to remain abstinent from cigarettes.
7.2.8.6
Participants will be compensated for completing the study visit and procedures.
7.2.9
Study Visit Reminders
Phone calls and/or text messages will be used throughout the study to remind participants of 
their next visits (approximately 1-2 days prior) (SEE VISIT SCRIPT ATTACHMENT). Also, visit 
time/date confirmation and study center directions will be emailed/mailed to the participant 
prior to Visit 1 (SEE FIRST VISIT REMINDER ATTACHMENT). 
7.3
Duration of Participation
Participants who complete the entire study will participate in the study for 7 weeks.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Nicotine orally dissolving films will be provided in doses of 0, 2, or 4 mg. The active 
pharmaceutical ingredient in these nicotine films is nicotine polacrilex (20%, USP). The film used 
in has a muco-adhesive property (i.e., it can adhere to the oral mucosa and allow the drug to be 
absorbed through oral mucosa). After placement in the oral cavity, the nicotine film dissolves 
over a 5 minute period. The unit-dose dosage is in the form of a 1 in x 1 in square and weighs 
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about 100 mg. Nicotine films are not available in the United States in a non-investigational 
setting. See table below for composition information.
Nicotine ODF Dosage
0 mg
2 mg
4 mg
Material Name
Grade
Weight, g
Weight, g
Weight, g
Sodium Bicarbonate
USP/EP
1.97
1.71
1.64
Propylene Glycol
USP/EP
23.66
20.55
19.68
Nicotine Polacrilex 20%
USP
0.00
17.81
37.72
Purified Water
USP 
209.04
205.45
196.80
Ethanol anhydrous
USP
110.44
119.85
114.80
Polyox N10 (Polyethylene oxide)
NF
134.10
116.42
111.52
Saccharin
Food Grade
2.45
2.12
2.03
Cocoa Powder 
Food Grade
1.77
1.71
1.97
L-Menthol
USP
9.98
8.66
8.30
Peppermint oil
USP
6.19
5.38
5.15
Methylparaben
NF
0.20
0.17
0.20
Propylparaben
NF
0.20
0.17
0.20
Total
 
500.00
500.00
500.00
7.4.2
Treatment Regimen
Nicotine films will be administered orally. They are used by placing a film on the tongue, closing 
the mouth, and pressing the tongue gently to the roof of the mouth. The film will dissolve in the 
mouth within 5 minutes. Three doses of nicotine film will be used in this study: 0, 2, and 4 mg.  
Participants will be randomized to one of three possible treatment regimens: 
1)
Random nicotine delivery (a combination of four 0 mg and 4 mg films daily not to 
exceed three non-consecutive 4 mg films in one day and to maintain an average of 
8mg of nicotine per day through 7 days for 6 weeks total)
a)
Possible weekly random delivery dosing scenarios to maintain an 8 mg/day 
average through 7 days:
a.
One 4mg day, five 8mg days, and one 12mg day in any order
b.
Two 4mg days, three 8mg days, and two 12mg days in any order
2)
Steady state nicotine delivery (2, 2, 2, 2 mg films daily for 6 weeks total)
3)
Placebo delivery (0, 0, 0, 0 mg films daily for 6 weeks total)
Participants will be directed to take one film every 3-4 hours, in a specified order, for a total of 
four films consumed daily. In the event that participants miss taking a scheduled film, they will 
be instructed to skip the film if more than 8 hours has passed since they took their last film. 
They will be asked to indicate on their daily diary if a film was missed..
Possible Daily Sequences for Random Delivery
4mg/day
8mg/day
12mg/day
4000
0400
0040
0004
4400
4040
4004
0440
0404
0044
4404
4044
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7.4.3
Method for Assigning Subject to Treatment Groups
Participants will be randomized to one of three dosing groups based on a predetermined 
random number sequence generated by the study statistician, Dr. Junjia (Jay) Zhu.  
7.4.4
Subject Compliance Monitoring
Participants will be given a paper daily diary to complete on which they will record: 1) the 
number of cigarettes smoked each day, and 2) the date and time of each nicotine film taken. 
Participants will be given detailed instructions on how to complete the diary. Questions will be 
asked at each contact to review participants’ logs and to verify their daily conventional cigarette 
and nicotine film use. Participants will also be asked to self-report their other tobacco use at 
each visit, including use of products such as electronic cigarettes, cigars, pipes, chew, snus, dip, 
hookah, and dissolvable tobacco. Exhaled carbon monoxide measurements will be collected 
throughout the study to verify smoking intensity.
Participants will be asked to return all of their used (empty/opened) and unused (unopened) 
nicotine film pouches to each study visit following Visit 2. At each of these visits, study staff will 
document the number of used and unused nicotine film pouches to verify participants’ film use 
and compliance. 
7.4.5
Blinding of the Test Article
Blinded packages of the nicotine films will be created for each participant by an unblinded 
pharmacy staff member. Both the participant and the researcher will be blinded to the assigned 
dosing regimen and to the doses of each film. 
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The nicotine films will be manufactured by Bionex Pharmaceuticals, LLC in its 
North Brunswick, NJ facility under cGMP conditions and shipped directly to Penn 
State Hershey Medical Center. The packaged test article has been tested to be 
stable at temperatures up to 30°C for 12 months, and therefore, will be shipped 
via courier under room temperature.
Each nicotine film will be individually packaged in a sealed, chemical- and 
moisture-resistant, multi-component (polyester/aluminized), laminated pouch.  
7.4.6.2
Storage
The nicotine films will be stored in the Investigational Drug Services (IDS) 
Pharmacy at the Penn State Milton S. Hershey Medical Center in accordance 
with guidelines provided by the manufacturer.
7.4.6.3
Preparation and Dispensing
The nicotine films will arrive in individually sealed, peel-apart pouches. They will 
be blinded by pharmacy staff who will appropriately package kits containing 
each daily nicotine film dosing regimen to last the participant until the end of 
their next study visit window. The four individual films within each daily 
regimen’s container will be numbered so that the films are taken in the 
appropriate sequential order each day. The blinded researchers will not be 
involved in the packing and labeling of the kits. All receiving, sorting, blinding of 
the study product will be done in IDS pharmacy space at Penn State.
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7.4.6.4
Return or Destruction of the Test Article
Participants will be required to return all study products to the research center 
at each clinic visit, including any empty/opened pouches using provided 
containers/bags. Any remaining nicotine films will be destroyed according to 
Penn State IDS Pharmacy protocol at the conclusion of the study.
7.4.6.5
Prior and Concomitant Therapy
Concomitant medication use will be collected at baseline and regularly 
throughout the study to serve as covariates during analysis and to monitor 
participant health conditions. Participants currently using FDA approved 
cessation medications will be excluded. Should a participant start a medication 
during the randomized, double-blind phase of the study that would interfere 
with their ability to participate, they may be withdrawn from the study.
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
Participants will be enrolled in the study until a total of 45 are randomized. We anticipate that we will 
need to enroll up to 70 participants in order to randomize 45.
8.2
Sample size determination
Previous studies have shown the effects of NRT on cessation in sample sizes that are comparable to 
(e.g., Foulds, et al., 1992; Rose, et al., 1998; Rose, et al., 2006) the one proposed here (n=15 per 
treatment arm). Based upon such work, we are confident that we will have sufficient power to achieve 
the aim of the proposed research.
8.3
Statistical methods
Paired sample t-tests (or nonparametric Wilcoxon Rank-Sum tests) will be used to examine changes in 
the outcome measures (CPD, CO, subjective measures, BP, HR) from baseline.
9.0
Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form.
9.1
Confidentiality
9.1.1
Identifiers associated with data and/or specimens
See the Research Data Plan Review Form.
9.1.1.1 Use of Codes, Master List
See the Research Data Plan Review Form.
9.1.2
Storage of Data and/or Specimens
See the Research Data Plan Review Form.
9.1.3
Access to Data and/or Specimens
See the Research Data Plan Review Form.
9.1.4
Transferring Data and/or Specimens
N/A
9.2
Subject Privacy
See the Research Data Plan Review Form.
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10.0 Data and Safety Monitoring Plan
10.1
Periodic evaluation of data
The study coordinator and the PI will be responsible for the daily oversight of subject safety. Medical 
history will be reviewed by the study staff, and based on eligibility criteria, any questionable medical 
histories will be brought to the attention of the medical monitor for final inclusion determination prior 
to randomization. In a similar manner, contraindications for the treatment products and vital signs will 
be checked by study staff at each in person visit. The medical monitor will be available via phone for any 
consultations as necessary.
Subjects will be under medical supervision while in the study (i.e., by the medical monitor) and seen on 
an ongoing basis by our research staff who will document adverse events. The medical monitor will 
assess all adverse events and will be available for consultation over the phone for urgent matters. 
Otherwise, the PIs and/or the medical monitor will meet weekly with the study staff to review patient’s 
progress and their experiences with the study products, including any adverse events.  
10.2
Data that are reviewed
Data that will be reviewed include:
• Accrual and retention
Medical history and concomitant medications
• Adverse events and serious adverse events
• Protocol deviations/violations
10.3
Method of collection of safety information
All data, including safety data, will be coded directly into REDCap electronic case report forms during 
study visits. Participant adverse events and serious adverse events will be assessed at each in-person 
study visit and each phone call visit but can be reported at any time during the study.
10.4
Frequency of data collection
Safety data, including adverse events and serious adverse events will be collected at each study contact.  
10.5
Individuals reviewing the data
The study coordinator and the PI will be responsible for the daily oversight of subject safety. The PI 
and/or the medical monitor will meet weekly with the study staff to review patients’ progress and their 
experiences with the study products, including any adverse events. For more urgent and/or serious 
adverse events, the medical monitor will be available for consultation by phone. The medical monitor 
will then make any needed medical recommendations and a determination regarding whether the 
participant is able to continue with the study.
10.6
Frequency of review of cumulative data
All of the data from the study (including adverse events) will be reviewed by the leadership group, 
including Dr. Sciamanna, on a regular basis to review patients’ progress and their experiences with the 
study products.
10.7
Statistical tests
Statistical methods will be used to analyze the safety data to determine whether harms are occurring. 
Paired sample t-test (or nonparametric Wilcoxon Rank-Sum test) will be used to examine the changes in 
the outcome measures (CPD, CO, subjective measures, BP, HR) from the baseline.
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10.8
Suspension of research
Due to the low risk of the intervention, it is unlikely that there will be a need to suspend the research.  
However, should the medical monitor, Dr. Sciamanna, identify any issues after reviewing the data, he 
can develop stopping rules for the trial, and his recommendations will be followed.
11.0 Risks
Potential risks for subjects are minimal. We have previously tested both single and repeat administration of each 
of the nicotine film doses which will be dispensed to subjects. We found that they were well-tolerated by 
subjects and produced nicotine levels in the blood that are less than subjects routinely receive from their 
cigarette smoking.19 Subjects will have a review of their medical history prior to entry into the study. Subjects 
will be under medical supervision throughout their participation in the study, and adverse symptoms will be 
recorded by the research staff and monitored by the medical monitor and PIs.  The major risks associated with 
the study are related to the use of nicotine (which is similar to the nicotine received from smoking) and nicotine 
withdrawal. 
Additional potential risks include:

Nicotine film side effects: Excess nicotine can cause mild symptoms such as nausea, dizziness, diarrhea, 
rapid heartbeat, heartburn, and hiccups. Occasionally these symptoms are more severe (e.g., vomiting) 
such as when an individual receives more nicotine than they are accustomed to. This, however, is 
unlikely to occur with the doses used in this study.

Nicotine withdrawal symptoms:  Ceasing conventional cigarette use may result in nicotine withdrawal 
symptoms (e.g., irritability, anxiety, restlessness, depressed mood, increased appetite, fatigue, difficulty 
concentrating). These symptoms will be monitored at each visit. Those receiving placebo films may 
experience more serious nicotine withdrawal symptoms. 

Risk to fetus and breast fed infants:  Nicotine is known to be harmful to the developing human fetus, 
either from cigarettes or at the dose being used in this study. Women who are pregnant or are nursing a 
child may not participate in this research study. Women capable of becoming pregnant will be 
administered a pregnancy test prior to beginning the research. Participants must agree to take 
reasonable and necessary precautions against becoming pregnant during the period of the investigation.

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: Participants will be assigned to a treatment program by chance. The research 
intervention they receive may prove to have more side effects than the other research intervention(s).

Discomfort from questionnaires:  It is possible that some of the questions in the questionnaires may 
make participants uncomfortable. Participants will be instructed that they are free to skip any questions 
that make them uncomfortable.

Possible effects on the oral cavity: Participants will be asked to report side effects including any mouth 
discomfort or irritation at each study contact. If indicated, a participant may discontinue study product 
use.

Incidental Finding:  None of the tests carried out in this study are intended to provide diagnoses for 
clinical purposes, but participants will be alerted to findings that should be discussed with a healthcare 
provider (such as high blood pressure).
12.0 Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
There is no guaranteed direct benefit to the individuals who participate in this study.  However, those 
who participate and who are able to successfully quit smoking will have less exposure to tobacco-related 
toxicants as a result of their participation.
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12.2
Potential Benefits to Others
Society as a whole will benefit from the research because it is expected to provide important 
information on the efficacy of nicotine film and random nicotine delivery as a potential method for 
smoking cessation. 
13.0 Sharing Results with Subjects
This study is not designed to diagnose any disease or condition.  However, if during the course of conducting 
clinical procedures (e.g., blood pressure), 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.  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, they will be 
withdrawn from the study, and they will be advised to follow up with their doctor for prenatal medical care.
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements
Total compensation for the study is $140, which will be paid in both gift cards and checks. Actual payment will 
vary according to the number and type of contacts completed by each subject. 
Participants will receive a $20 Walmart gift card upon completion of each in-person study visit. Those who 
complete all in-person study visits and who comply with the study product pouch return protocol (accurate 
returned pouches within a margin of 3 pouches at each visit following randomization) will receive a compliance 
incentive of $25. The compliance incentive will be paid in a check mailed to the participant’s home upon 
completion of Visit 5.
Compensation for each completed phone call will be $5, for a potential total of $15, which will be paid in a 
cumulative check mailed to the participant’s home only upon completion of Visit 5. If a participant did not 
complete any phone calls during the study, or if they did not complete Visit 5, they will not receive any of the 
potential $15 phone call compensation.
Time & Events Table
Study Visit # 
1
2
Ph #1
3
Ph #2
4
Ph #3
5
Study Week #
0
1
2
3
4
5
6
7
Payment method
GC*
GC*
GC*
GC*
GC/CH*
Payments
$20
$20
Potential 
$5
$20
Potential 
$5
$20
Potential 
$5
$20 gift card
+ up to $15 for phone calls
+ $25 compliance incentive
Total
$20
$20
$20
$20
$60
*GC=Gift Card, CH=Check
15.0 Economic Burden to Subjects
15.1
Costs 
There will be no costs to the subjects for any of the procedures or tests associated with the study.  
Participants will be provided with the study products at no cost. Participants and/or their insurance 
companies will not be responsible for costs related to study procedures and tests.
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.
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16.0 Resources Available
16.1
Facilities and locations
All participant visits will take place in the Penn State Hershey Clinical Research Center.
16.2
Feasibility of recruiting the required number of subjects
The smoking prevalence in South Central Pennsylvania is 19% of the adult population. Our recruitment 
strategy is designed to broadly disseminate information about the study to members of the community.
16.3
PI Time devoted to conducting the research
Drs. Grigson and Foulds have no clinical responsibilities and so the majority of their time is devoted to 
research, including this project. They are each funded at 5% time to this study.
16.4
Availability of medical or psychological resources
All of our participants will be seen by appropriately trained research staff. Any serious AEs or concerning 
test results will be passed on to participants along with a letter to their doctor. Any urgent health 
problem will require accompanying the participant to the ER, which is located in the same building as 
the clinical research center.
16.5
Process for informing Study Team
Regular team meetings will be conducted where study procedures, questions, and issues will be 
discussed and resolved.
17.0 Other Approvals
17.1
Other Approvals from External Entities
The FDA will require submission of an amendment to a previously approved IND (Investigational New 
Drug) application.
17.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy). 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.  
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  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
18.0 Multi-Site Research
18.1
Communication Plans
N/A
18.2
Data Submission and Security Plan
N/A
18.3
Subject Enrollment
N/A
18.4
Reporting of Adverse Events and New Information
N/A
18.5
Audit and Monitoring Plans
N/A
19.0 Adverse Event Reporting
19.1      Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
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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 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.
19.2
Recording of Adverse Events
Research subjects will be routinely questioned about adverse events at in-person study visits and during 
scheduled phone contacts.
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study drug(s) or device(s) 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
o
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.
19.3
Causality and Severity Assessments
The medical monitor, Dr. Sciamanna, will promptly review documented adverse events and abnormal 
test findings on a weekly basis 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. For more 
urgent and/or serious adverse events, the medical monitor will be available for consultation by phone. 
The medical monitor will then make any needed medical recommendations and a determination 
regarding whether the participant is able to continue with the study.
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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 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
19.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
19.4.1 Written IND/IDE Safety Reports
The Sponsor-Investigator will submit a written IND Safety Report (i.e., completed FDA Form 
3500A) to the responsible new drug review division of the FDA for any observed or volunteered 
adverse event that is determined to be a serious and unexpected, suspected adverse reaction.  
Each IND Safety Report will be prominently labeled, “IND Safety Report”, and a copy will be 
provided to all participating investigators (if applicable) and sub-investigators.
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no event, 
later than 15 calendar days following the Sponsor-Investigator’s receipt of the respective 
adverse event information and determination that it meets the respective criteria for reporting.
For each written IND Safety Report, the Sponsor-Investigator will identify all previously 
submitted IND Safety Reports that addressed a similar suspected adverse reaction experience 
and will provide an analysis of the significance of newly reported, suspected adverse reaction in 
light of the previous, similar report(s) or any other relevant information.
Relevant follow-up information to an IND Safety Report will be submitted to the applicable 
review division of the FDA as soon as the information is available and will be identified as such 
(i.e., “Follow-up IND Safety Report”).
If the results of the Sponsor-Investigator’s follow-up investigation show that an adverse event 
that was initially determined to not require a written IND Safety Report does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will submit a written IND Safety Report as 
soon as possible, but in no event later than 15 calendar days, after the determination was made.
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
In addition to the subsequent submission of a written IND Safety Report (i.e., completed FDA 
Form 3500A), the Sponsor-Investigator will notify the responsible review division of the FDA by 
telephone or facsimile transmission of any unexpected, fatal or life-threatening suspected 
adverse reaction. 
The telephone or facsimile transmission of applicable IND Safety Reports will be made as soon 
as possible but in no event later than 7 calendar days after the Sponsor-Investigator’s receipt of 
the respective adverse event information and determination that it meets the respective criteria 
for reporting.
19.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
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19.6
Unblinding Procedures
If an adverse event requires the subject to be unblinded, the unblinded study personnel (pharmacy 
staff) will be able to provide that information as needed. This will be reported appropriately along with 
the adverse event in accordance with the safety monitoring plan. Otherwise, participants will not be 
unblinded to their assigned study condition.
19.7
Stopping Rules
In the event of unexpected or serious adverse events that the study doctor, Dr. Sciamanna, believes are 
related to the study product, the IRB will be notified, and their recommendations will be followed.
20.0 Study Monitoring, Auditing and Inspecting
20.1
Study Monitoring Plan
20.1.1 Quality Assurance and Quality Control
The study will be monitored by the Clinical Trial Monitoring Team from the Department of 
Public Health Sciences at Penn State Hershey College of Medicine. The monitors will provide an 
independent review of the regulatory and subject records and the data collected to assure 
compliance with the protocol, GCP, and applicable federal regulations. The monitoring will occur 
at regular intervals after the enrollment of the first subject and the times will be predetermined 
by the monitoring plan developed by the Clinical Trial Monitoring Team.
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 (i.e., consent) will be securely transported to the PI’s data entry 
center.  Any additional data that is generated 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 (e.g., 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 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 
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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.  
20.1.2 Safety Monitoring
The principal investigator will confirm that all adverse events (AEs) are correctly entered into the 
AE case report forms by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; and will notify the IRB, FDA, and/or sponsor of all 
applicable AEs as appropriate. All assessments of AEs will be made by a licensed medical 
professional who is an investigator on the research study.
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 sponsor of all Unanticipated Problems/SAEs.
21.0 Future Undetermined Research: Data and Specimen Banking
21.1
Data and/or specimens being stored
N/A
21.2
Location of storage
N/A
21.3
Duration of storage
N/A
21.4
Access to data and/or specimens
N/A
21.5
Procedures to release data or specimens
N/A
21.6
Process for returning results
N/A
22.0 References
1.
Jamal A, Phillips E, A.S. G, et al. Current Cigarette Smoking Among Adults — United States, 2016. 2018.
2.
Services USDoHaH. The Health Consequences of Smoking: 50 Years of Progress.  A Report of the Surgeon General. 
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 
National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health 2014.
3.
Borland R, Partos TR, Yong HH, Cummings KM, Hyland A. How much unsuccessful quitting activity is going on 
among adult smokers? Data from the International Tobacco Control Four Country cohort survey. Addiction. 
2012;107(3):673-682.
4.
Etter JF, Stapleton JA. Nicotine replacement therapy for long-term smoking cessation: a meta-analysis. Tobacco 
control. 2006;15(4):280-285.
5.
Ferguson SG, Shiffman S. The relevance and treatment of cue-induced cravings in tobacco dependence. J Subst 
Abuse Treat. 2009;36(3):235-243.
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6.
Wilson SJ, Sayette MA, Delgado MR, Fiez JA. Instructed smoking expectancy modulates cue-elicited neural 
activity: a preliminary study. Nicotine & tobacco research : official journal of the Society for Research on Nicotine 
and Tobacco. 2005;7(4):637-645.
7.
Wilson SJ, Sayette MA, Delgado MR, Fiez JA. Effect of smoking opportunity on responses to monetary gain and 
loss in the caudate nucleus. J Abnorm Psychol. 2008;117(2):428-434.
8.
Ponce LF, Pautassi RM, Spear NE, Molina JC. Ethanol-mediated operant learning in the infant rat leads to 
increased ethanol intake during adolescence. Pharmacol Biochem Behav. 2008;90(4):640-650.
9.
Twining RC, Bolan M, Grigson PS. Yoked Delivery of Cocaine Is Aversive and Protects Against the Motivation for 
Drug in Rats. Behav Neurosci. 2009;123(4):913-925.
10.
Donny EC, Bigelow GE, Walsh SL. Comparing the physiological and subjective effects of self-administered vs 
yoked cocaine in humans. Psychopharmacology. 2006;186(4):544-552.
11.
Mello NK, Mendelson JH. Experimentally induced intoxication in alcoholics: a comparison between programed 
and spontaneous drinking. J Pharmacol Exp Ther. 1970;173(1):101-116.
12.
Shiffman S, Ferguson SG. Nicotine patch therapy prior to quitting smoking: a meta-analysis. Addiction. 
2008;103(4):557-563.
13.
Lindson N, Aveyard P. An updated meta-analysis of nicotine preloading for smoking cessation: investigating 
mediators of the effect. Psychopharmacology. 2011;214(3):579-592.
14.
Rose JE. Nicotine preloading: the importance of a pre-cessation reduction in smoking behavior. 
Psychopharmacology. 2011;217(3):453-454.
15.
Rose JE, Behm FM. Adapting smoking cessation treatment according to initial response to precessation nicotine 
patch. Am J Psychiatry. 2013;170(8):860-867.
16.
Foulds J, Stapleton J, Feyerabend C, Vesey C, Jarvis M, Russell MA. Effect of transdermal nicotine patches on 
cigarette smoking: a double blind crossover study. Psychopharmacology. 1992;106(3):421-427.
17.
Tan HS, Chung SL, Inventors. Dual and single layer dosage forms. US patent 9,019,718 B2. April 28, 2015.
18.
Tan HS. Oral transmucosal drug delivery system for nicotine. Paper presented at: 14th Annual Duke Nicotine 
Research Conference, 2008; Durham, NC.
19.
Lester C, Hammett E, Veldheer S, et al. Single-Dose Pharmacokinetics of Nicotine from an Orally Dissolving 
Nicotine Film. Submitted for publication. 2018.
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