Conditions: Tobacco Use Disorder
Keywords: Ramelteon Nicotine Nicotine dependence Insomnia Tobacco Dependence
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 140
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled crossover study to test whether a medication called ramelteon (Brand Name: Remeron) will help smokers quit and whether it reduces sleep problems that smokers experience during a quit attempt.

Detailed description:
Ramelteon, an FDA-approved treatment for insomnia, is used to treat sleep problems (e.g., specifically sleep onset latency) by enhancing melatonin receptor function. The investigators propose a randomized double-blind placebo-controlled crossover study.

Fifty chronic smokers will complete a validated procedure for screening new medications. All subjects will receive 8mg ramelteon and placebo. The order in which ramelteon and placebo is received will be randomized across participants. This is a 6-week study consisting of two 2-week medication phases separated by a 2-week washout. Each phase includes 1 week of ad libitum smoking (baseline) and 1 week of medication (ramelteon vs. placebo) plus transdermal nicotine patches while trying to abstain from smoking (quit assessment). Subjects will complete the same procedures during each study phase. Following completion of the study, participants will be offered standard smoking cessation treatment.

For the duration of the study, subjects will be asked to keep sleep diaries and to wear an armband while sleeping, which provides objective indices of sleep duration and quality (SensewearPro® armband).

The primary outcome will be the total number of days abstinent (out of 5) during each quit assessment period. Intermediate outcomes include sleep onset latency (self-report) and sleep efficiency (SensewearPro®).

This study will provide information about the role of the melatonin system during brief abstinence and whether enhancing melatonin reduces abstinence-induced sleep problems that promote smoking relapse. Information obtained in this study may further establish the role of sleep disturbance in promoting smoking relapse.

Arms:
arm 1: The study will be performed using 8mg of ramelteon, which is currently marketed for the treatment of sleep problems. The proposed study follows the typical dosing regimen for ramelteon (8mg once a day) for 5 days during each quit assessment period.

Ramelteon will be purchased and packaged into blister packs by the Investigational Drug Service (IDS) at the University of Pennsylvania. In accordance with FDA recommendations, subjects will be instructed to take study medication within 30 min prior to going to bed and avoid taking study medication with or immediately after a high fat meal. arm 2: 5-day placebo-controlled medication period.

Placebo ingredients will be purchased, encapsulated, and packaged into blister packs by the IDS at UPenn. Both active medication and placebo will look identical.

The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take ramelteon during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by ramelteon during the second medication period.

Interventions: intervention 1: Ramelteon intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
         University of Pennsylvania    Institutional Review Board 
 
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IRB APPLICATION 
Template Version: 23 April 2010  
Application for Review of Human Research: IRB Protocol Summary 
Biomedical Research 
Version 9, 07/16/18 
 
 
Names of Investigators: 
Name 
Department  (all at UPenn) 
Rebecca Ashare, Ph.D., Principal Investigator  
3535 Market Street, Suite 4100,  
Philadelphia, PA 19104     
215-746-5789 
rlashare@pennmedicine.upenn.edu 
Psychiatry 
David Dinges, Ph.D., Co-I 
Psychiatry 
Janet Audrain-McGovern, Ph.D., Co-I 
Psychiatry 
Frank Leone, MD, Ph.D., Study Physician 
Psychiatry 
 
PROTOCOL TITLE 
1.  Full Title 
Repurposing melatonin receptor agonists as adjunct treatments for smoking cessation. (NCT02560324) 
 
2.  Brief Title 
Effect of ramelteon on smoking abstinence 
 
STUDY SPONSORSHIP 
1.  Funding Sponsor 
National Institute on Drug Abuse (R21 DA040902) 
 
2.  Primary Sponsor 
Caryn Lerman, Ph.D., Director, CIRNA 
 
PROTOCOL ABSTRACT 
There is a need for novel approaches to optimize smoking cessation treatment to help more smokers quit. Sleep 
disturbance during nicotine withdrawal may be an important treatment target since existing treatments do not 
mitigate withdrawal-related sleep disturbance and difficulty sleeping predicts smoking relapse. We hypothesize 
that the FDA-approved melatonin receptor agonist, ramelteon, combined with transdermal nicotine replacement 
therapy (TN), will promote abstinence by attenuating withdrawal-related sleep disturbance. Using a well-validated 
medication screening paradigm, we propose a within-subject, placebo-controlled crossover design with one 
within-subjects factor of medication (ramelteon vs. placebo). Treatment-seeking smokers (n=50) will complete this 
6-week study (two 2-week phases separated by a 2-week washout). Each phase includes 1 week of ad libitum 
smoking (baseline) and 1 week of medication (8mg ramelteon or placebo) plus TN while trying to abstain (quit 
assessment). Small monetary incentives will be provided for biochemically-confirmed abstinence. Subjects will 
keep daily sleep diaries and wear an armband while sleeping which provides objective indices of sleep 
(SensewearPro®). The primary outcome will be the number of biochemically-confirmed days abstinent (out of 
five). Intermediate outcomes include sleep onset latency (self-report) and sleep efficiency (SensewearPro® 
armband). These data will lay the foundation for a larger Phase IIb clinical trial.    
 
 
OBJECTIVES 
1.  Overall Objectives 
The objective of this proof-of-concept pilot study is to evaluate ramelteon as a potential smoking cessation aid in 
treatment-seeking smokers. 
 
2.  Primary Outcome Variable(s)  
The primary outcome is the total number of days abstinent (biochemically verified) during a 5-day quit attempt.  
 
3.  Secondary Outcome Variable(s)  


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a. Sleep disturbance measures (sleep onset latency and sleep efficiency) with ramelteon treatment vs. placebo.  
b. Predicting the ability to remain abstinent during the 5-day quit assessment week based on reduction in 
withdrawal-related sleep disturbance. 
 
BACKGROUND 
There is a Critical Need for Novel Smoking Cessation Treatments. Despite the fact that cigarette smoking 
continues to be the greatest preventable cause of morbidity and mortality, there are currently only three FDA-
approved medications for nicotine dependence: nicotine replacement therapy (NRT; transdermal nicotine (TN), 
nasal spray, gum, lozenge), bupropion, and varenicline. Although TN doubles the odds of smoking cessation 
compared to placebo, the majority relapse within the first week [1, 2]. Importantly, we demonstrated that each 
additional day of abstinence during the first week nearly doubles the odds of success at end-of-treatment [3]. 
There is a clear need to identify novel approaches to optimize treatment to help more smokers maintain 
abstinence during this critical period. The development of a clinically valid model  for early human screening of 
medications to treat nicotine dependence [4-6], coupled with an emphasis on “repurposing” existing medications, 
provides a practical approach to achieve this aim [7, 8]. These models can also be used to assess novel smoking 
cessation treatment targets, such as sleep disturbance.  
Sleep Disturbance is a Treatment Target. Converging lines of evidence suggest that remediating sleep 
disturbance may be a novel therapeutic target as an adjunct treatment for nicotine dependence. First, nicotine 
withdrawal is associated with sleep disturbance, such as difficulty falling asleep and increased number of 
awakenings [9-11]. Second, existing nicotine dependence treatments do not mitigate sleep problems during a quit 
attempt; in fact, we and others have shown that TN [12-15] and varenicline [16] may exacerbate the problem. 
Third, sleep disturbance predicts smoking relapse in clinical trials and laboratory models of relapse [17-19]. Our 
preliminary data demonstrate that smokers who report longer sleep onset latency and wake more often are 
abstinent for fewer days using a model of short-term abstinence.   
Medications to Improve Sleep as a Smoking Cessation Treatment. Pharmacotherapies that improve sleep 
may be efficacious adjunct smoking cessation treatments. However, FDA-approved medications for insomnia 
including 
benzodiazepines 
(e.g., 
zolpidem/Ambien®) 
and 
hypnotics 
(e.g., 
eszopiclone/Lunesta®, 
zaleplon/Sonata®) may produce next-day residual effects, such as memory impairment, difficulty concentrating, 
or mood symptoms [20], that may promote smoking relapse [21, 22]. The FDA-approved melatonin receptor 
agonist, ramelteon (Rozerem®; RAM) does not produce next-day residual effects, has a low abuse potential, is 
not classified as a controlled substance, and is safe to use with TN [23]. Critically, RAM is indicated for improving 
sleep onset latency (SOL), which is commonly reported among smokers [9, 24] and associated with abstinence in 
a model of short-term abstinence. We hypothesize that RAM, combined with TN, will promote smoking cessation 
by reducing withdrawal-related sleep disturbance. 
 
Using a well-validated medication screening paradigm [4-6], we propose a within-subject, placebo-controlled 
crossover design with one within-subjects factor of short-term medication (ramelteon vs. placebo). Treatment-
seeking smokers (n=50) will complete this 6-week study, which consists of two 2-week phases separated by a 2-
week washout. Each phase includes 1 week of ad libitum smoking (baseline) and 1 week of medication (8mg 
ramelteon or placebo) plus TN while trying to abstain (quit assessment). For the duration of the study, subjects 
will be asked to keep sleep diaries and to wear an armband while sleeping, which provides objective indices of 
sleep duration and quality (SensewearPro®). Subjects will receive standard TN following completion of the study. 
The primary outcome will be the total number of days abstinent (out of 5), a measure that is highly predictive of 
longer-term quit success [3]. Intermediate outcomes include sleep onset latency (self-report) and sleep efficiency 
(SensewearPro®). 
 
CHARACTERISTICS OF THE STUDY POPULATION 
1. Target Population 
Fifty adult, treatment-seeking smokers, between the ages of 18-65, reporting consumption of at least 10 cigarettes 
per day for at least the past 6 months will be the target population for the study. 
 
2.  Accrual 
In order to have 50 smokers complete all sessions, we will enroll (consent) 150 participants. We anticipate 
approximately 50% (n=75) of those who consent will meet final eligibility criteria. Of the 75 who are eligible, we 


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conservatively estimate 25% attrition to have 50 smokers complete the study. Participants will first be screened 
over the phone and then complete an in-person Intake to ensure final eligibility. Enrolled participants will be 
randomized to receive ramelteon and placebo in counterbalanced order. Participants will be told that this study 
includes two practice quit attempts with an FDA-approved medication that is being tested as a possible new 
treatment for smoking cessation.  
 
3.  Key Inclusion Criteria  
Smokers ages 18-65, who have smoked at least 10 cigarettes per day for the past 6 months, will be eligible to 
participate. They must be able to provide informed consent, and express interest in quitting smoking in the next 2 
to 4 months. Using a scale from 0 to 100, they must rate their confidence that they will make a quit attempt in the 
next 2 months a 50 or higher. Following the current study, participants will be referred to a free smoking cessation 
program.  Those who wish to quit sooner can be referred directly to another program. 
 
4.  Key Exclusion Criteria 
Subjects who self-report and/or present with the following criteria will not be eligible to participate in the study. 
 
Smoking Behavior: 
1. Current enrollment in a smoking cessation program, or use of other smoking cessation medications in the 
last month or plans to do either in the next 2 months. 
2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes. 
3. Provide a carbon monoxide (CO) breath sample reading less than 10 parts per million (ppm) at Intake. 
 
Alcohol/Drugs:   
1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the past 6 months. 
Subjects will be told to limit or avoid the use of alcohol while in the study to avoid any adverse reactions to 
the study medication. 
2. Self-reports substance use disorders (abuse or dependence involving alcohol, opiates, cocaine or other 
stimulants, or benzodiazepines; not nicotine) in the last 6 months.  
3. Self-reports daily use of marijuana. Individuals who report occasional use must agree to refrain from use 
for the duration of the study. 
4. Providing a breath alcohol concentration (BrAC) reading of greater than or equal to 0.01 during any 
session.  
5. A positive urine drug screen for cocaine, amphetamines, methamphetamines, benzodiazepines, PCP, 
methadone, barbiturates, marijuana, ecstasy (MDMA), oxycodone, tricyclic antidepressants, and opiates 
(low level cut-off 300 ng/mL) during any session. 
 
Psychiatric Exclusion (as determined by self-report on phone screen, through MINI, and/or the Columbia Suicide 
Severity Rating Scale (C-SSRS) during Intake): 
1. Current psychiatric disorders (depression, bipolar, schizophrenia, hypomanic/manic episode) as 
determined by self-report and/or MINI psychological interview. 
2. Past history of psychiatric disorders (including suicide attempt) other than depression as determined by 
self-report and/or MINI psychological interview.  
3. Suicide risk score on MINI greater than 1. 
4. Current (past month) suicidal ideation or lifetime suicidal behavior on the C-SSRS. 
 
Medical:   
1. Females who are currently pregnant, planning a pregnancy during the study, or currently 
breastfeeding/lactating. All female subjects shall undergo a urine pregnancy test at the Intake and must 
agree in writing to use an approved method of contraception. Following enrollment, pregnancy tests will be 
conducted at the end of each baseline week. 
2. For those with a history of jaundice/liver disease: liver function tests more than 20% outside of the normal 
range and/or Gamma-glutamyl Transpepsidase (GGT) values more than 20% outside of the normal range. 
If Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be evaluated for clinical 
significance by the Study Physician and eligibility will be determined on a case-by-case basis. 
3. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in the past 6 months. 
4. Endocrine or metabolic disorders (e.g., Type-I diabetes). 


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5. Blood disorders (e.g., anemia or hemophilia). 
6. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than 99)*. 
7. Clinically significant dyssomnia (except insomnia; e.g. sleep apnea syndrome, narcolepsy) [25, 26].  
 
* Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99 mmHg at the Intake visit 
will be instructed to sit quietly for 10 minutes. Then the participant will have a second blood pressure reading 
taken after a 10 minute period. If, after the second reading the SBP greater than 159 mmHg and the DBP greater 
than 99 mmHg, the individual will  be instructed to sit comfortably for 10 minutes and then have a third blood 
pressure reading. If, after the third reading the SBP greater than 159 mmHg and the DBP greater than 99 mmHg, 
the individual will be ineligible to participate. 
 
Medication:   
1. Current use or recent discontinuation (within the past month) of any of the following medications: 
a. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam). 
b. Anti-psychotic medications (e.g., thorazine, Seroquel). 
c. Mood-stabilizers (e.g., Lithium, Lamictal/lamotrigine, valproic acid, Neurontin/gabapentin, 
Topamax/topiramate, Tegretol/carbamazepine). 
d. Prescription stimulants (e.g., Provigil, Ritalin, Adderall). 
e. Medications contraindicated with ramelteon (e.g., fluvoxamine, donepezil, doxepin, buprenorphine 
or other medications metabolized by certain cytochrome P450 enzymes) 
f. Hormonal birth control that contains ethinyl estradiol  
g. Other medications containing ethinyl estradiol 
2. Current use or recent discontinuation (within the past 2 weeks) of any of the following medications 
(subjects must agree to refrain from using any other sleep aids while enrolled in the study): 
a. Sleep medications (e.g., zolpidem/Ambien, eszopiclone/Lunesta) [25, 26] 
b. Over-the-counter sleep aids (e.g., melatonin, diphenhydramine/Benadryl) 
3. Daily use of opiate-containing medications for chronic pain (Duragesic/fentanyl patches, Percocet, 
Oxycontin). Smokers who report taking opiate-containing medications on an “as-needed” basis will be 
instructed to refrain from use until their study participation is over and informed that they will be tested to 
ensure they have complied with this requirement. 
4. Known allergy to study medication (e.g., angioedema). 
 
Subjects will be instructed to refrain from using any study prohibited drugs/medications (both recreational and 
prescription) throughout their participation in the study.  After final eligibility is confirmed, subjects who report 
taking contraindicated medication(s) over the course of the study period may only remain eligible if the Study 
Physician and/or Principal Investigator determines that the contraindicated medication(s) do/did not impact the 
study design, data quality, and/or subject safety/welfare. Subjects are permitted to take necessary prescription 
medications not included within the exclusion list during the study. 
 
General Exclusion: 
1. Current, anticipated, or pending enrollment in another research program over the next 2-3 months that 
could potentially affect subject safety and/or the study data/design as determined by the Principal 
Investigator and/or Study Physician. 
2. Not planning to live in the area for the next two months. 
3. Currently working night shift or rotating shift or other habitual alteration of the sleep/wake cycle [26]. 
4. Allergy to latex or adhesive tape. 
5. Inability to provide informed consent or complete any of the study tasks as determined by the Principal 
Investigator. 
6. Not able to effectively communicate in English (reading, writing, speaking). 
7. Missing 2 or more doses during the medication period determined by self-report. 
 
5.  Vulnerable Populations  
No children under the age of 18, pregnant women, fetuses, neonates, or prisoners are included in this research 
study.   
 
6.  Populations vulnerable to undue influence or coercion 


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Educationally or economically disadvantaged persons or cognitively impaired persons will be not be targeted for 
recruitment; however, they may be included in the current study. Because recruitment efforts for this study will be 
targeted to the greater Philadelphia area, University of Pennsylvania employees and students, and UPHS faculty 
and staff may be exposed to these advertisements and choose to respond. These individuals are eligible to 
participate if they meet all inclusion criteria. Status of participation in the current study will be independent of the 
participant’s work or school activities. 
 
7.  Subject Recruitment  
Participants will be recruited from two sources.  Participants who have previously completed studies at our center 
and have agreed to be re-contacted for future studies will be contacted and invited to participate in this study. 
Additional recruitment via TV, newspaper, radio, poster, and internet-based advertising (e.g., in-app ads, 
Craigslist, and iConnect) will be used to invite smokers from the general population.    
 
STUDY DESIGN 
1.  Phase 
Phase: II Randomized, double-blind, placebo-controlled trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Design 
We propose to conduct a randomized, placebo-controlled, cross-over design with one within-subjects factor of 
medication (RAM vs. PLA; order counterbalanced). Each phase includes: 1 week of ad libitum smoking (baseline) 
and 1 week of medication (8mg RAM or PLA) plus TN while trying to abstain (quit assessment) (Figure 1). 
 
3. Study Duration  
Estimated length of time to enroll all subjects and complete the study 
Enrollment will start in October 2015 (after IRB approval is received). We estimate that we will need to telephone 
screen 1500 smokers to enroll (consent) 150 smokers into the study (accounting for 10% eligibility). Using a 
conservative estimate of attrition (50%), we expect to have 50 participants complete all sessions and study 
requirements. We estimate enrolling 4-5 smokers per month. 
 
Length of a subject’s participation time in study 
We estimate it will take a minimum of 7 weeks for a participant to complete the entire study. However, this time 
period may be longer to accommodate participant schedules or scheduling difficulties between the Intake and 
phase 1 and the duration of the washout period. Thus, the maximum duration a participant can be in the study is 
12 weeks.  
 
Projected date of completion of the proposed study  
We estimate that 50 people will have completed the study by March 2018, and that analyses and reporting will be 
complete by August 2018. 
 
Figure 1. Overview of Study Design 
PHASE 
INTAKE 
STUDY PERIOD 1 
WASHOUT 
STUDY PERIOD 2 
WEEK  
# 
 
0 
Baseline 
1 
Quit Week 
2 
 
3-4 
Baseline 
5  
Quit Week 
6 
STUDY VISITS 
X 
 
M 
 
W 
 
F 
 
M 
TQD 
T 
 
W 
 
TH 
 
F 
 
NONE 
 
M 
 
W 
 
F 
 
M 
TQD 
T 
 
W 
 
TH 
 
F 
 
MEDICATION 
NONE 
*RAM plus TN or 
PLA plus TN 
NONE 
WASHOUT 
*RAM plus TN or 
PLA plus TN 
ACTIVITY 
 
Medical  
History 
Psych Screen 
Monitoring 
Visits 
Sleep 
Monitoring 
Observation  
Assessments 
Sleep Monitoring 
NONE 
Monitoring 
Visits 
Sleep 
Monitoring 
Observation 
Assessments 
Sleep Monitoring 
SMOKING 
STATE 
Smoking Ad Libitum 
Monitored 
Abstinence 
Smoking Ad Libitum 
Monitored 
Abstinence 
* Treatment (RAM vs PLA) order randomized and counterbalanced across subjects; All subjects receive transdermal 
nicotine (TN). TQD=Target Quit Date 


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DRUGS OR DEVICES 
Ramelteon 
The study will be performed using 8mg of ramelteon, which is currently marketed for the treatment of sleep 
problems.  
 
The proposed study follows the typical dosing regimen for RAM (8mg once a day), which is documented to be 
safe and well-tolerated [27-29]. Ramelteon will be purchased and packaged into blister packs by the 
Investigational Drug Service at the University of Pennsylvania. In accordance with FDA recommendations, 
subjects will be instructed to take study medication within 30 min prior to going to bed and avoid taking study 
medication with or immediately after a high fat meal.  
 
An IND exemption has been approved for this study for ramelteon and TN as the results will not be reported to the 
FDA to support a new drug indication. 
 
Supply, Preparation, Storage, Packaging and Dispensing of Study Medication 
Ramelteon will be purchased and supplied via the University of Pennsylvania Investigational Drug Service (IDS 
number pending). Matched placebo will be made in-house using sucrose filler in gel capsules. The IDS will store 
the medication as per the manufacturer guidelines. Specifically, medication will be stored at room temperature (20 
– 25 degrees centigrade) and in airtight containers. Ramelteon and the matching placebo will be packaged in 
blister packs.  IDS will oversee the labeling of all study medication, and will assign each kit, which contains 
medication for one subject, a unique Pharmacy Randomization Number (PRN). 
 
Kits will be ordered as needed by the research staff and stored in a locked cabinet at our center. Once the Study 
Physician (Dr. Leone) signs the prescription and a subject is assigned a treatment order (ramelteon first or 
placebo first), medication kits will be ordered and picked up from IDS by a member of the research staff. Once a 
new subject is enrolled and eligible, the research staff will assign the subject the next available PRN. Blister packs 
will then be labeled with the subject’s study ID number. Each medication kit will consist of 6 days of 8mg 
ramelteon and 6 days of placebo (one for each quit assessment day plus an extra). The PRN and study ID 
number must match for each blister pack a subject receives. Medication will be stored at CIRNA as per 
manufacturer’s guidelines. 
 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining. This reconciliation will be logged on the drug reconciliation form, and signed by the research staff 
member who completed the reconciliation. 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated by the research 
staff. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files. 
 
Transdermal Nicotine 
Subjects will receive the 21 mg dose during each quit-assessment week. The patch will be Nicoderm CQ as used 
in our previous clinical trials [30, 31]. Subjects will be given the patches at the last visit during each Baseline week 
(weeks 1 and 5) and instructed to begin using the patches the morning of the TQD during each study period 
(Figure 1). Because wearing nicotine patches at night may cause sleep disturbance (i.e., vivid dreams) [32-34]), 
subjects will be instructed to remove the patch before going to sleep. Following completion of the study, we will 
offer all subjects open-label cessation treatment with TN to attract participation by smokers with strong motivation 
to quit. 
 
All patches will be purchased from a University of Pennsylvania approved vendor (GlaxoSmithKline). Upon 
receipt, an inventory will be performed and a drug receipt log will be completed and signed by the person 
accepting the shipment. Study staff will count and verify that the shipment contains all the items noted in the 
shipment inventory. To ensure patch inventory is kept up to date, an on-going inventory will also be performed as 


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patches are distributed. Patches will be stored in a double locked location (i.e., in a locked cabinet in a locked 
room) at room temperature. 
 
SUICIDAL IDEATION AND BEHAVIOR 
The C-SSRS will be administered at the Intake visit by a trained member of the staff. Individuals who endorse 
current (past month) suicidal ideation or lifetime suicidal behavior will be ineligible to participate. Because these 
assessments may cause an adverse emotional reaction, staff will be trained to deal with such reactions and to 
provide additional referrals if needed. If necessary, referrals to appropriate psychological services will be 
provided.  
 
STUDY PROCEDURES 
1.  Procedures 
This is a randomized placebo-controlled study of the effects of ramelteon, compared to placebo, on ability to quit 
smoking. Participants will complete an Intake at the Center for Interdisciplinary Research on Nicotine Addiction 
(CIRNA) before being enrolled into the study. All study visits will be completed at the CIRNA. Participants will 
complete two 2-week phases separated by a two-week washout period. Each phase will involve one week of ad 
libitum smoking (Baseline) and one week of medication (RAM vs. PLA) as well as TN treatment while trying to 
abstain (Quit Assessment). Each Baseline week, subjects will attend a brief visit on Monday, Wednesday, and 
Friday to assess smoking rate, blood pressure, CO and BrAC samples, side effects, withdrawal, craving, and 
affect. Subjects’ sleep diaries will be collected and the SensewearPro® data will be downloaded to confirm 
compliance. During the quit assessment weeks, subjects will take the assigned study medication on each 
weekday and urine samples will be collected to confirm compliance. They will be asked to try their best to abstain 
from smoking will receive $10/day for each day that self-reported abstinence is biochemically-confirmed 
(CO<5ppm). They will complete 20-min visits on each weekday to verify abstinence and complete measures. 
 
2. Study Visits 
 
Telephone Screening. Individuals interested in participating will be screened by an experienced research 
technician to determine initial study eligibility. If the subject meets preliminary phone eligibility and is interested 
in participating, he/she will be invited to attend a 2.5-hour Intake visit. Subjects will be contacted via phone 
call, text message, e-mail, and/or postal mail to remind them about their scheduled intake visit date and time. 
Method of preference will be collected over the phone. 
 
 
Intake (Week 0). In this 2.5-hour visit, participants will have their eligibility confirmed (using the previously 
detailed inclusion/exclusion criteria listed above). A schedule of activities for the day include: 
1. Arrive at the CIRNA and hear detailed description of the study and have any questions answered by a 
staff member from the CIRNA 
2. Complete combined study consent/HIPAA form  
3. Provide urine specimens for drug and (if applicable) pregnancy tests. Participants who test positive for 
either the urine drug screen and/or pregnancy test will be ineligible. 
4. Provide CO breath sample. Participants must have CO readings greater than or equal to 10ppm in 
order to be eligible for the study 
5. Provide BrAC measurements. Participants must  have readings less than 0.01 in order to be eligible 
for the study  
6. Provide a blood pressure reading (See Blood Pressure Procedures under Screening/Covariate 
Measures) 
7. Complete routine medical history (self-report) with a member of the research staff 
8. Complete a psychological interview  (MINI) and the C-SSRS with a trained research staff member 
(Description under Screening/Covariate Measures) 
9. Complete brief physical examination (led by a medical professional) 
10. Have height and weight measured (led by study staff) 
11. For individuals who report a history of jaundice/liver disease: provide an 8.5ml blood sample drawn for 
the assessment of liver function (LFTs and GGT enzyme levels). They will receive final confirmation of 
eligibility via phone call based on the liver function tests. 
 


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If a participant is ineligible due to any of the above criteria during the Intake, he/she will only be 
compensated $10 for travel. However, if a participant tests positive for study prohibited drugs, he/she will 
not receive any compensation. 
 
Otherwise, if a participant meets the above eligibility criteria at the Intake, he/she will be asked to complete 
the following:  
 
12. Complete questionnaires (demographics, nicotine dependence, smoking rate, withdrawal, and 
smoking urges) 
13. Receive instructions on how to record their daily sleep diaries and report their sleep and wake times 
14. Be randomized to receive RAM or PLA during the first phase 
15. Finalize their study schedule 
  
Participants will be asked to refrain from using any study prohibited drugs (note: participants are allowed 
to take prescription medications not in the exclusion list) throughout their participation in the study. Female 
participants will also be asked to use an approved method of contraception through the study. 
 
 
Final Eligibility Phone Call (only for individuals with a history of jaundice/liver disease). When liver function 
tests have been reviewed and authorized by the Study Physician, a study staff member will call the subjects to 
inform them of their final eligibility.  
 
Final Eligibility is defined as: Liver function test results and GGT liver enzyme levels that are no more than 
20% outside the normal, clinical range. Albumin/Globulin ratios 20% outside of normal range will be evaluated 
for clinical significance by the Study Physician and eligibility will be determined on a case-by-case basis. 
 
Ineligible subjects may be referred to other studies at our center.  Eligible subjects will schedule all other study 
visits and be randomized to receive RAM or PLA during the first phase. During the first study visit, participants 
will receive instructions on how to use the SensewearPro® and record their daily sleep diaries.  
 
 
Baseline Weeks (Weeks 1 and 5). Participants will complete three observation visits during the Baseline 
weeks on Monday, Wednesday, and Friday. The visits on Monday and Wednesday will last approximately 20 
minutes. The start of the first phase can be scheduled within 2 days of the Intake but no more than 30 days 
can elapse between Intake and start of the first phase. At the observation visits participants will: 
 
1. Arrive at CIRNA and provide a CO and BrAC sample (Participants must have BrAC readings less than 
0.01 in order to be eligible for the study). 
2. Provide a blood pressure sample (See Blood Pressure Procedures under Screening/covariate 
measures). 
3. Complete questionnaires (smoking rate, concomitant medication review, sleep, withdrawal, smoking 
urges, mood, and side effects). 
4. Have sleep diaries collected and data stored on armband downloaded by research technician. 
Research staff will review adherence. 
 
At the first (Monday) visit of Baseline Week 1 and 5, the participant will receive his or her SensewearPro® 
armband. At Baseline Week 1, the participant will receive an instructional packet and a research staff 
member will review how to use the armband and charger correctly. 
 
The third (Friday) visit of each Baseline Week will last approximately 40 minutes. During this visit, subjects 
will: 
1. Provide urine specimens for drug and (if applicable) pregnancy tests (Friday visit only).  Participants 
who test positive for either the urine drug screen and/or pregnancy test will be withdrawn from the 
study. 


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2. Meet with a smoking cessation counselor for a 20-min coaching session to prepare them for the 
practice quit attempt. The counselor will review coping strategies for managing triggers and withdrawal 
symptoms.  
3. Participants will receive their study medication and nicotine patches. Study staff will review instructions 
for taking the study medication and applying the nicotine patches. 
 
These sessions can be scheduled for any time of day. Ideally, the subsequent sessions would be at the 
same time of day, but can be scheduled up to 3 hours earlier or later. However, the sessions may go 
beyond 3 hours as determined by PI discretion. 
 
 
Quit Assessment Weeks (Weeks 2 and 6). Participants will attend a 20 minute study visit every weekday of 
their quit assessment week. They will be asked to bring their study medication to this visit to verify medication 
adherence/pill counts. During this session, which will last approximately 20 minutes, participants will complete 
measures of: 
1. Blood pressure (See Blood Pressure Procedures under Screening/covariate measures) 
2. CO breath sample 
a. To increase abstinence motivation, participants will receive $10/day (in cash) for each day for 
self-reported abstinence that is biochemically-confirmed. On Monday, a CO reading of less 
than 10ppm or less than 50% of CO breath sample taken during the Baseline week will be 
sufficient as biochemically-confirmed abstinence. At all other visits, a CO reading less than 5 
ppm will be considered as biochemically-confirmed abstinence. 
3. BrAC sample 
4. Smoking rate (timeline followback; TLFB)  
5. Medication adherence (pill count)  
6. Side effects and concomitant medication review 
a. If moderate to severe adverse events are reported, the PI/Study Physician will be consulted 
and a decision will be made as to whether to proceed with the study. 
7. Mood, smoking urges, withdrawal symptoms, sleep measures  
 
At the last visit of the first Quit Assessment Week (Week 2), the SensewearPro® armband and charger 
will be collected from the participant, as he or she will not be using the SensewearPro® armband during 
the washout period. If the participant continues the study, the participant will receive the SensewearPro® 
armband at their first visit of the second Baseline Week (Week 5). 
 
These sessions can be scheduled for any time of day. Ideally, the subsequent sessions would be at the 
same time of day, but can be scheduled up to 3 hours earlier or later. However, the sessions may go 
beyond 3 hours as determined by PI discretion. 
 
At the final visit of the study, participants will be offered information (i.e. flyer, brochure, etc.) about a 
smoking cessation research program at the CIRNA. If no cessation studies are available or the participant 
does not wish to participate, they will be provided a list of referrals to other cessation programs in the 
greater Philadelphia area (e.g., the Comprehensive Smoking Treatment Program at UPenn Presbyterian). 
The participant’s decision whether or not to receive this information will be documented. Participants will 
return the SensewearPro armband and will be given a summary report of their physical activity and sleep 
patterns. 
 
 
Washout Weeks (Weeks 3 and 4): During these two weeks, participants will not have any study visits or take 
any study medication. They will be instructed to smoke ad libitum. Subjects who abstain during week 2 will be 
required to resume smoking during week 3 to remain in the study. Subjects will be told that they may withdraw 
from the study if they choose not to resume smoking. We expect few subjects to discontinue the study for this 
reason [4, 35, 36]. 
 
 
 


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3. Description of Measures and Variables   
 
3.1 Screening/Covariate Measures 
Demographics and Smoking History. Standard questionnaires will be self-administered at the Intake visit to collect 
the following data: demographics (age, gender, marital status, education), age at smoking initiation, cigarette brand, 
length of prior abstinence periods and current smoking rate.  The Fagerstrom Test for Nicotine Dependence (FTND) 
will also be administered.  The FTND is a 6-item, self-report measure of nicotine dependence derived from the 
Fagerstrom Tolerance Questionnaire [37].  The FTND scale has satisfactory internal consistency (Cronbach's 
alpha=. 64) and high test-retest reliability (r=. 88) [38]. 
 
Medical History. A medical history (self-report) and a physical examination will be conducted at the Intake visit to 
review for any contraindications listed previously. The medical history (including height and weight) will be 
completed by a research staff member.  
 
Psychiatric History. Current major depression, lifetime prevalence of psychosis, bipolar disorder, schizophrenia, 
hypomanic/manic episodes, and substance abuse will be determined via self-report during the phone screen and 
via semi-structured interview using the Mini International Neuropsychiatric Interview (MINI). The MINI is a 10-15 
minute structured interview developed by the World Health Organization to assess major DSM-IV Axis 1 
psychiatric diagnoses. This instrument permits both current (past 30 days) and lifetime assessments of psychiatric 
illness, and recent data support its reliability and validity [39]. The MINI will be administered by a trained research 
staff member at the Intake visit. There will be 100% review of paper MINIs by Dr. Hole, a clinical psychologist with 
relevant training, to maintain quality control. 
 
Suicidal Behavior and Ideation (C-SSRS). All participants will complete the C-SSRS (Screening Version) with a 
trained staff member at the Intake Visit. The C-SSRS is a structured interview that assesses the suicidal behavior 
and suicidal ideation in subjects [40, 41]. Occurrence of lifetime suicidal behavior is defined as having answered 
“yes” to at least 1 of the 4 suicidal behavior sub-categories (actual attempt, interrupted attempt, aborted attempt, 
and preparatory acts or behavior). Current suicidal ideation is defined as having answered “yes” to at least 1 of 
the suicidal ideation sub-categories (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation 
with any methods without intent to act, active suicidal ideation with some intent to act [without specific plan], and 
active suicidal ideation with specific plan and intent) over the past month. 


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Table 1. Measures and Time Points. 
Activity (Week #) 
Intake  
Baseline (1 & 5) 
Quit Assessment (2 & 6) 
Day 
0 
Mon 
Wed 
Fri 
Mon 
Tue 
Wed 
Thu 
Fri 
TREATMENT 
 
 
 
 
 
 
 
 
 
Ramelteon (RAM) or Placebo 
 
 
 
 
Xa 
Xa 
Xa 
Xa 
Xa 
Transdermal Nicotine (TN) 
 
 
 
 
X 
X 
X 
X 
X 
SCREENING/COVARIATES  
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
Smoking History/FTND 
X 
 
 
 
 
 
 
 
 
Medical/ ETOH History (self-report) 
X 
 
 
 
 
 
 
 
 
Psychiatric History (Self-report and MINI) 
X 
 
 
 
 
 
 
 
 
Suicidal Behavior/ Ideation (C-SSRS) 
X 
 
 
 
 
 
 
 
 
Urine drug/pregnancy screen 
X 
 
 
X 
 
 
 
 
 
Breath alcohol  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood draw (liver function tests)b 
X 
 
 
 
 
 
 
 
 
Brief counseling 
 
 
 
X 
 
 
 
 
 
TREATMENT VARIABLES 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RAM Adherence (pill count) 
 
 
 
 
X 
X 
X 
X 
X 
TN Adherence 
 
 
 
 
X 
X 
X 
X 
X 
Side Effects (TN and RAM) 
 
X 
X 
X 
X 
X 
X 
X 
X 
INTERMEDIATE OUTCOMES  
 
 
 
 
 
 
 
 
 
Sleep Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pittsburgh Sleep Quality Index (PSQI) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep efficiency (SensewearPro) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Depression Symptoms (CESD) 
X 
 
 
X 
 
 
 
 
X 
Withdrawal, Craving, Affect 
 
X 
X 
X 
X 
X 
X 
X 
X 
SMOKING OUTCOMES   
 
 
 
 
 
 
 
 
 
Cessation/Smoking Rate (TLFB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carbon Monoxide (CO) Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Note. No visits or assessments during washout (weeks 3-4). FTND=Fagerstrom Test for Nicotine Dependence; 
CESD= Center for Epidemiological Studies on Depression; TLFB=Timeline Followback 
a study medication taken the previous night; b only for those with a history of jaundice/liver disease 
Urine Drug Screen. The urine drug screen will be administered at Intake and the last visit of each baseline week 
(Friday of weeks 1 and 5).  The urine drug screen requires about 30ml of urine and indicates whether the subject 
has recently taken any exclusionary drugs (marijuana, cocaine, PCP, amphetamines, methamphetamines, 
tricyclic antidepressants, ecstasy, opiates, methadone, benzodiazepines, and barbiturates). Participants with a 
positive urine drug screen for any substance listed above will be deemed ineligible. In an effort to remain CLIA-
compliant, results from urine drug screening will not be shared with participants. Participants will be informed that 
the testing is for research purposes only and that they will be informed of their eligibility status, but not of the 
specific testing results.  
 
Urine Pregnancy Test. At the Intake and the last visit of each baseline week (Friday of weeks 1 and 5), 
participants will be supplied with a simple, CLIA-waived urine pregnancy screen and informed that pregnant 
women are not advised to participate in this research study. Participants will then be instructed to administer the 
pregnancy test independently and will inform study staff if they would like to continue participation after they have 
administered the pregnancy screen. Participants will be informed that there is no penalty for discontinuing 
participation at this point in the visit and that they will still receive travel reimbursement for the visit. 
 
Breath Alcohol Concentration.  The breath alcohol concentration (BrAC) assessment will be administered at the 
Intake visit and all subsequent study visits. The breath alcohol monitor assesses expired breath for alcohol 
content. A reading greater than or equal to 0.01 at any session indicates alcohol consumption within the last 14 
hours and will result in the participant being withdrawn from the study.  
 


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Blood Pressure.  At the Intake, participants presenting with elevated blood pressure (i.e., systolic blood pressure 
greater than 159 and/or diastolic blood pressure greater than 99) will have a second blood pressure reading taken 
after a ten minute period in which the participants will be instructed to sit comfortably.  If, after the second reading 
the SBP is greater than 159 mmHg and/or the DBP is greater than 99 mmHg, the individual will  be instructed to 
sit comfortably for 10 minutes and then have a third blood pressure reading. If, after the third reading the SBP is 
greater than 159 mmHg and/or the DBP is greater than 99 mmHg, the individual will be ineligible to participate. 
 
Blood pressure will be measured at all subsequent in-person visits.  If participants present with elevated blood 
pressure (i.e., systolic blood pressure greater than 159 mmHg and/or diastolic blood pressure greater than 99 
mmHg) at any subsequent visit, the staff will follow the same steps listed above. If, after a third reading, systolic 
blood pressure remains greater than 159 mmHg and/or diastolic remains greater than 99 mmHg, the subject will 
be told to not take the next dose of study medication. If a participant presents with a SBP between 151-159 
mmHg and/or DBP between 91-99 mmHg at the Intake or any visit during a Baseline week, the research staff will 
inform the participant that they have mild, Stage I, hypertension and advise they consult with a physician. The 
participant will remain eligible for the study and receive nicotine patches as scheduled. The research staff will 
notify the Study Physician/Health Care Provider who will review the blood pressure reading and determine 
whether it is safe for the subject to continue. Research staff will follow up with the participant accordingly. 
 
Liver Function Tests and Gamma-glutamyl Transpepsidase. Only individuals with a history of jaundice/liver 
disease will provide a blood sample for liver function tests. One 8.5ml blood sample will be drawn at the Intake 
visit to conduct liver function tests.  Blood will be collected and placed in a serum-separator tube (SST) and mixed 
thoroughly.  Samples will be centrifuged at 3000 rpm for 15 minutes.  The following chemistry will be assessed:  
1. Total protein. 
2. Albumin. 
3. Globulin. 
4. Albumin:Globulin ratio. 
5. Bilirubin (total, conjugated and unconjugated) 
6. Aspartate amino transferase (AST). 
7. Alanine amino transferase (ALT). 
8. Alkaline phosphatase (AP). 
9. Gamma glutamyl transferase (Gamma-GT). 
 
Brief counseling. These 20-minute sessions will occur during the final visit of each Baseline week (Friday). This 
counseling session will be similar to previous studies in our center (IRB#815789). Specifically, a trained smoking 
cessation counselor will review reasons for smoking and common withdrawal symptoms. Counselors will work 
with participants to develop plans to manage triggers, avoid cigarettes, and gather social support. Participants will 
also be taught a breathing relaxation technique for handling stressful situations. 
 
3.2 Treatment Variables 
 
Concomitant Medication Review.  Subjects will be asked about their use of medications (over the counter and 
prescription) and substances that may alter subjects’ response to the study medication.  The Study 
Physician/Health Care Provider will advise as to whether other medications being taken are contraindicated and 
prescribe appropriate action from there (i.e., discontinuation of the study medication). The concomitant medication 
review will be completed at every study visit following the Intake. 
 
Pill Count/Adherence. Medication adherence will be assessed by pill count at each study visit or telephone 
session [42]. We will assess patch use by participants’ self-report and collect unused patches at the end of the 
week. 
 
Side Effects. A checklist of side effects based on the product insert will be administered to participants at all study 
visits after the Intake. The frequency and severity of common side effects of RAM [43] and TN [30, 44] will be 
rated on a 0 (none) to 3 (severe) scale. An open-ended side effects question will also be included. Furthermore, 


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participants will receive written instructions to call the Health Care Provider/Study Physician should they experience 
any severe side effects or adverse events between study visits.   
 
3.3 Intermediate Outcomes 
 
Subjective Sleep Measures: As in Dr. Dinges’ prior work, subjects will complete sleep diaries daily within 1h of 
getting out of bed and prior to going to sleep and will provide time-stamped phone records for time to bed and 
time awake [45-48]. These well-validated sleep diaries assess subjective SOL, total sleep time, number of 
awakenings and perceived quality of sleep. The diaries will be used to verify the sleep parameters derived from 
the SensewearPro® armbands [49, 50]. 
The Pittsburgh Sleep Quality Index (PSQI) is a 9-item measure that assesses the quality and patterns of sleep 
over the past month. It measures seven areas: subjective sleep quality, sleep latency, sleep duration, habitual 
sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. Scoring is based on a 0 to 
3 scale, whereby 3 reflects the negative extreme. A sum of “5” or greater indicates a “poor” sleeper [51]. The 
PSQI has good internal consistency (α=0.83), validity, and reliability, and is sensitive to treatment [52, 53]. The 
outcome is the global PSQI score and will be evaluated as a moderator of RAM’s effects on abstinence.  
Sleep Efficiency (SensewearPro armbands): A multi-method approach is necessary to capture different 
components of insomnia symptoms [54], such as self-report, polysomnography (PSG) or actigraphy [50]. 
Compared to PSG, actigraphy provides concordance rates between 80% and 95% for wake/sleep detection, 
enables data collection for weeks to months, and is less expensive [50, 55, 56]). The SensewearPro® armbands 
(BodyMedia, Inc. Pittsburgh, PA) measure body movement, like actigraphy, and acquire additional physiological 
signals, including surface body temperature, galvanic skin response, and heat flux [57]. The armbands provide 
89% concordance with PSG data and identify sleep and wakefulness with moderate to high sensitivity and 
specificity [57]. Subjects will wear the armband during each phase (weeks 1, 2, 5, and 6), and will be provided 
$4/day for each day they wear the armband and complete the sleep diary plus $50 if they provide at least 18 of 22 
days of data (85%). Subjects will be instructed to remove the armband only for bathing purposes or water activity. 
The data will be downloaded to the Sensewear Professional software (v8.0; Bodymedia, Pittsburgh, PA) at each 
visit to confirm compliance using a threshold of 90% on body time. Following PSG standards, the first and last 
nights will not be analyzed to allow for adaptation [50, 55, 56]. The outcome is sleep efficiency. Participants will 
not be responsible for lost or otherwise compromised armbands. 
 
Depression symptoms. The 20-item Center for Epidemiological Studies on Depression scale (CESD) will assess 
depressive symptoms [58, 59]. It has high internal consistency (α=0.85) and scores greater than16 correlate with 
clinical ratings of depression [60]. Participants will rate the intensity of their symptoms in the past week on the 
following scale: 0 = rarely, or none of the time (less than once a day), 1 = some, or a little of the time (1-2 days), 2 = 
occasionally, or a moderate amount of time (3-4 days), 3 = most, or all of the time (5-7 days) and a summary score 
will be calculated. The CESD will be administered at the Intake and on the last visit of each Baseline and Quit 
Assessment week. 
 
Withdrawal Symptoms. The “Minnesota Nicotine Withdrawal Scale - Revised version”(MNWS_R) [61] captures 
the current state of nicotine withdrawal [62, 63]. The scale assesses eight DSM-IV items of nicotine withdrawal 
including: dysphoria or depressed mood, insomnia, irritability/frustration/anger, anxiety, decreased heart rate, 
difficulty concentrating, restlessness, and increased appetite/weight gain.  Participants will rate the intensity of their 
symptoms on the following scale: 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe and a summary score will 
be calculated. This will be administered at all study visits (except the Intake). Withdrawal will be assessed using a 
24-h time reference for all visits following the Intake.  
 
Craving. The 10-item brief QSU questionnaire on smoking urges [64] will be used to assess craving for cigarettes 
during the medication run-up period.  The QSU-B contains 2 subscales (anticipation of reward, relief from 
negative affect).  Craving has also been related to long-term cessation outcome in many, but not all, clinical 
studies [65]. This will be administered at all study visits (except the Intake). Similar to withdrawal symptoms, craving 
will be assessed using a 24-h time reference at all visits following the Intake.  
 


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Mood: Positive and Negative Affect.  The Positive and Negative Affect Schedule (PANAS) [66], a 20-item Likert-
format self-report measure, will be used to assess Positive Affect (PA; 10 items, e.g., enthusiastic, strong) and 
Negative Affect (NA; 10 items, e.g., distressed, upset), two dominant and generally orthogonal dimensions of 
affect. PA and NA (PANAS) will be assessed at all study visits (except the Intake). PA and NA will be assessed 
using a 24-h time reference for all visits following the Intake.  
 
3.4 Smoking Outcomes 
 
Smoking Rate (TLFB).  We will assess the number of cigarettes smoked on each day throughout the study. A 
standard timeline follow-back (TLFB) method will be used [67], as we have done previously [68] to assess self-
reported smoking rate. During each quit week, abstinence will be assessed daily by self-report of no smoking at 
all over the prior 24 hours and an expired-air CO less than 5 ppm (except for the Monday visit when CO may be 
less than 10ppm or less than 50% Baseline CO). This stringent biochemical criterion for validating smoking 
cessation has been shown to be more sensitive to detect smoking and specific to verify abstinence than higher 
CO cut-offs [69]. 
 
Carbon Monoxide.  Carbon monoxide (CO) measures will be made using a Vitalograph Breath CO Analyzer 
(McNeil International, Inc., Lenexa, KS).  The manufacturer will have calibrated this device within the past year.  A 
new, disposable cardboard mouthpiece will be provided for each participant.  The device has a digital screen 
which reports CO levels in parts per million (ppm).  Participants will be asked to provide a CO breath sample by 
taking a large breath then exhaling twice. Then, they will take another deep breath and hold their breath for 10 
seconds, as per the recommendations of the American Thoracic Society.  Then, when instructed to do so, 
participants will exhale as forcefully and as long as they are comfortably capable.  The largest value displayed is 
recorded during all CO breath samples. CO breath samples will be collected at each study visit. At the Intake, 
participants must have CO readings greater than or equal to 10ppm in order to be eligible for the study.   
 
2.  Statistical Analysis 
Sample size.  
Effect sizes for power analyses were derived from prior work on TN effects on days of abstinence (Aim 1) [6], 
studies demonstrating RAM’s effects on sleep (Aim 2), and our preliminary data. All significance levels will be set 
at 0.05. Our primary hypothesis is that RAM will increase the number of days abstinent (out of 5), compared to 
placebo. In prior validation work, the average number of days abstinent for TN was 2.0±0.3 [6]. Fifty subjects 
provide 80% power to detect a difference of 0.55 days between RAM and PLA, using a SD of 1.36 and a within-
subjects correlation of 0.78 [31].  
 
For Aim 2, meta-analyses indicate that RAM is associated with reducing SOL by 4.3 min and increasing sleep 
efficiency by 4.42% [70]. Our preliminary data suggest that TN increases sleep disturbance by 58% (d=0.28) in 
abstinent smokers and that abstinence increases SOL by ~5 min and decreases sleep efficiency by ~5%. Fifty 
subjects provide 80% power to detect differences of 6 min in SOL and 5% in sleep efficiency between RAM and 
PLA, using a within-subject correlation between 0.4 and 0.8. Thus, Aims 1 and 2 are sufficiently powered. 
 
Statistical Analysis.  
 
For Aim 1 (H1), a within-subject ANOVA will test the primary hypothesis for effects of RAM (vs. PLA) on number 
of days abstinent during the quit week.  
 
For Aim 2 (H2a), separate 2 drug (RAM vs. PLA) x 2 week (baseline vs. quit week) repeated measures ANOVAs 
will test the effects of RAM on SOL and sleep efficiency. Drug and week are within-subject factors and sleep 
measures will be averaged across days within each baseline and quit week. We are primarily interested in the 
drug x week interaction to test whether RAM (vs. placebo) attenuates sleep disturbance during the quit week, 
relative to baseline. Thus, each period has its own baseline control comparison. A supplemental analysis will 
include only days during the quit week when subjects are abstinent.  
 
For Aim H2b, linear regression models will test whether sleep disturbance predicts number of days abstinent and 


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whether this relationship varies by treatment. Models will include covariates (e.g., baseline depression/anxiety, 
FTND, sex, and age). We will also examine correlations between sleep disturbance data and nicotine withdrawal 
and depression/anxiety symptoms in both groups. 
 
3.  Confidentiality 
All participant information will be kept in a secure filing cabinet that is accessible only to authorized study 
personnel.  All study databases containing participant information will be password protected, and accessible only 
to authorized study personnel.  Any study communications made by e-mail will use ID numbers and not include 
names or other personal information. All data sets will use ID numbers only.  
 
How will confidentiality of data be maintained?  Check all that apply. 
 
 Paper-based records will be kept in a secure location and only be accessible to personnel involved in the 
study. 
 Computer-based files will only be made available to personnel involved in the study through the use of access 
privileges and passwords. 
 Prior to access to any study-related information, CIRNA personnel will be required to sign statements agreeing 
to protect the security and confidentiality of identifiable information. 
 Whenever feasible, identifiers will be removed from study-related information.  
 A Certificate of Confidentiality will be obtained, because the research could place the subject at risk of criminal 
or civil liability or cause damage to the subject’s financial standing, employability, or liability. 
 A waiver of documentation of consent is being requested, because the only link between the subject and the 
study would be the consent document and the primary risk is a breach of confidentiality.  (This is not an option for 
FDA-regulated research.)  
 Precautions are in place to ensure the data is secure by using passwords and encryption, because the 
research involves web-based surveys.   
 Audio and/or video recordings will be transcribed and then destroyed to eliminate audible identification of 
subjects.  
 Other (specify):     
 
All research personnel associated with this study have completed the CITI-Protection of Human Subjects 
Research Training as well as HIPAA Compliance Training. Trained staff will assess eligibility, introduce the study 
rationale, procedures, study risks, and collect combined informed consent/ HIPAA authorization form.  
 
5. Privacy 
The following protected health information will be collected as part of this study: 
 
Name 
 
Street address, city, county, zip code 
 
Telephone numbers 
 
Email address 
 
Date of birth 
 
Medical and drug use history 
 
Last 4 digits of Social Security Number 
 
Results from all questionnaires, tests, or procedures 
 
Data collected from SensewearPro armbands 
 
Urine for drug screening/pregnancy test 
 
Blood for liver function test (for those with history of jaundice/liver disease) 
 
 
6.  Tissue Specimens 
Urine. A urine sample will be required at all sessions for the drug and pregnancy screening. Participants who test 
positive for study prohibited drugs use will be deemed ineligible, as will women who have a positive pregnancy 
test. All female participants of child-bearing potential will complete urine pregnancy tests.  
 
Blood. (only for those with history of jaundice/liver disease) An 8.5ml sample of blood will be drawn at the Intake 
visit to evaluate liver function. 
 
RISK/BENEFIT ASSESSMENT 
1.  Potential Study Risks 
Potential Risks of the Medication: The following are the common side effects that have been reported with 
ramelteon treatment:  drowsiness, tiredness, dizziness, and nausea. All of these side effects have been mild and 


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transient in nature. These symptoms have occurred in approximately 3% of subjects in clinical trials (Takeda 
Pharmaceutical, 2005).  Side effects will be assessed at baseline of each period and each subsequent visit (a 
total of 16 times throughout the study). The incidence of side effects is lower with the 8mg dose (as compared to 
the 16mg dose); which is the dose that has been selected in the proposed project. 
  
In addition to the side effects mentioned above, other rare side effects of ramelteon have been reported: 
 
 
Severe anaphylactic and anaphylactoid reactions such as angioedema (swelling of the tongue and larynx), 
difficulty swallowing, vomiting, and throat closing.  
 
Abnormal thoughts and behavioral changes such as hallucinations, suicidal thoughts, bizarre behavior, 
agitation and mania, amnesia, and anxiety 
 
Complex behaviors such as "sleep-driving" and other behaviors (e.g., preparing and eating food, making 
phone calls) 
 
Hormone effects including decreased testosterone and increased prolactin  
 
All of these side effects shall be queried using a side effects checklist as described above. 
 
Stringent exclusion criteria are in place to limit the chance of these side effects. Additionally, participants will be 
informed about these possible side effects and be made aware to watch for any of these symptoms and report 
them as soon as possible to the research staff. All subjects will be instructed to take the study medication 30 
minutes before going to bed. They will also be warned they should not drive or operate machinery after taking 
ramelteon and that they should limit their consumption of alcohol. All side effects will be closely monitored and the 
study physician consulted should moderate or severe side effects be reported. In case any participant 
experiences severe side effects or an adverse event, they will be encouraged to contact the study physician (Dr. 
Leone) and study PI (Dr. Ashare) immediately for appropriate intervention. The study physician’s emergency 
contact numbers shall be on the medication blister pack, the study consent form, and a study brochure all 
participants will be provided with once they enroll into the study.  
 
Transdermal Nicotine (TN) Replacement Therapy: All participants will receive transdermal nicotine (TN) patch 
therapy to aid in quitting smoking. This therapy is available over the counter and is very well tolerated. 
Participants will use the 21 mg patch for 5 days during each quit assessment week. Nausea, vomiting, weakness, 
dizziness, and rapid heartbeat occur rarely and are most often caused by continuing to smoke while using the 
patch. In addition, there is a risk of peptic ulcer formation and delayed wound healing associated with nicotine 
replacement therapies. Some individuals who use the patch experience minor skin irritation, such as redness, 
rash, or minor swelling, and insomnia and dream abnormalities. Because sleep problems are a primary 
mechanism of interest, participants will be instructed to remove the patch during the night while sleeping to avoid 
dream abnormalities. All of these reactions cease once the patch is removed. 
 
During the third visit of each baseline week (weeks 1 and 5), a member of the research staff will review the 
purpose of using the nicotine patch (e.g., to help manage withdrawal symptoms; not a substitute for behavioral 
quitting strategies), provide directions on how to use the patch (e.g., abstinence from smoking, patch location, 
time, activity, and potential skin reactions), and answer any questions.  
 
Because increased blood pressure is a side effect of TN patch therapy, blood pressure will be closely monitored 
at each visit. Expanding the upper limit of the blood pressure to less than 160/100 does not increase the risk to 
subjects enrolled in this trial. The risk of increased blood pressure is no greater than the risk from smoking and 
quitting smoking will lower an individual’s risk. If a participant presents with a SBP between 151-159 mmHg 
and/or DBP between 91-99 mmHg at the Intake or Pre-Quit visit, the research staff will inform the participant that 
they have mild, Stage I, hypertension and advise they consult with a physician. The participant will remain eligible 
for the study and receive nicotine patches as scheduled. 
 
Participants will complete a patch side effects checklist at each visit (in addition to those listed above for 
ramelteon). The PI will review the checklists for serious and persistent side effects. These will be communicated 
immediately to the study physician, Dr. Leone. Participants will be instructed to promptly discontinue the patch 
and contact the PI if they experience severe or persistent local skin reactions (e.g., severe redness, itching, or 
swelling) at the site of patch application or a generalized skin reaction (e.g., raised patches, hives, or generalized 
rash). Any serious adverse reactions or significant side effects of TN will be medically evaluated by the study 
physician. Patch use by such individuals will be monitored and adjusted as needed. Based on our previous 


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experience with NRT studies [30, 31], we expect few serious adverse events. Nevertheless, the study physician, 
Dr. Leone, will be available to assist with any adverse events and participant safety issues. Depending on the 
nature of the side effects, Dr. Leone may reduce the dose of the patch or recommend that the participant 
discontinue the patch. 
 
Pregnancy: In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic 
effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. There are no 
adequate and well-controlled studies in pregnant women. Thus, ramelteon must not be used during pregnancy. 
All female participants of child bearing potential must have a negative pregnancy test at the Intake session and 
prior to receiving study medication (Baseline Visit 3 of each medication period). 
 
Blood Draw: (only for individuals with a history of liver disease/jaundice) Blood draws may result in bruising and/or 
slight bleeding at the needle site.  This is rare and happens infrequently.  Occasionally, blood drawing results in a 
feeling of faintness.  This too is rare.  A trained professional will draw blood, so the chances of these discomforts 
are minimal. 
 
Confidentiality and Loss of Privacy: Protection of privacy of subjects in research studies is of utmost importance, 
particularly when health history information is collected. Information will never be recorded with identifiers other 
than study ID. A separate list of names with ID numbers will be accessible only by the database manager. All 
records will be kept in locked filing cabinets to maintain confidentiality. Results will not be communicated to other 
personnel or to the subjects. All analyses will be conducted on de-identified data. 
 
Withdrawal: Many individuals who smoke cigarettes exhibit a pattern of symptoms associated with withdrawal 
from cigarette use. These symptoms can include: sadness and anxiety, irritability, difficulty concentrating, anger, 
appetite change and weight gain, insomnia, and decreased heart rate. These events are generally of low risk. The 
study personnel will be trained to recognize these symptoms and educate the participants about them (e.g., their 
duration, methods for reducing them). TN will also help reduce withdrawal symptoms. 
 
Assessments: Subjects may experience emotional distress during assessments, from discussing feelings and 
attitudes about smoking, or from learning about the risks from smoking. These events happen very rarely and in 
almost all cases are short-lived and of low intensity. Study personnel will be alerted to expect this from a small 
number of subjects and will be trained to make referrals for mental health services as needed. Personnel will be 
trained to query for adverse emotional reactions during assessments and will be trained to deal with such 
reactions and to provide additional referrals if needed. In addition, if assessments indicate psychiatric concerns, 
referrals to appropriate psychological services will be provided. 
 
2.  Potential Study Benefits 
Participants who enroll in this study will benefit from the knowledge that they are contributing in an important way 
to potentially furthering scientific knowledge concerning ways to improve smoking cessation treatment. All 
smokers will receive standard treatment with TN to aid them in their effort to quit smoking and will learn skills to 
stay quit as a result of participating. 
 
3.  Alternatives to Participation 
At any point in the study participants may decide not to continue in their participation. As an alternative to 
enrolling in this study, participants may choose to continue to smoke or to seek assistance with quitting smoking 
through other treatment programs located in the area, other quit-smoking studies at our Center, or contacting the 
national quit-line. 
 
4.  Data and Safety Monitoring 
Who will monitor this study? Check all that apply. 
 Principal Investigator 
 Sponsor or contract research organization 
 NCI sponsored cooperative group 
 Cancer Center (if mandated by CTSMRC) 
 Medical monitor 
 Safety monitoring committee 


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 Data and safety monitoring board 
 
4.1 Data and Safety Monitoring Committee 
Data and Safety Monitoring will be conducted by the Principal Investigators and the Study Physician. They will 
review all possible Adverse Events (AEs) and Serious Adverse Events (SAEs). They will ensure that this 
information is captured in a comprehensive manner and reported according to Good Clinical Practice (GCP). The 
Principal Investigators, Study Physician, and the research staff will oversee and complete the monitoring process.  
Monitoring will be performed on an ongoing basis in accordance with the University of Pennsylvania Sponsor-
Investigator Standard Operating Procedure PM 504. 
 
The Principal Investigators are responsible for: 
1. Obtaining IRB review and approval of a clinical investigation before the investigation is initiated and 
ensuring continuing review of the study by the IRB in accordance with 21 CFR Part 56; 
2. Obtaining informed consent in accordance with 21 CFR Part 50; and 
3. Assuring that all staff and subjects understand and accept the obligations incurred in undertaking this 
double-blind placebo-controlled study in accordance with 21 CFR Parts 312, 511, 812, 813 and any 
other applicable regulations.  
 
The research staff is responsible for collecting and recording all clinical data.  This includes ensuring that all 
source documents exist for the data on the Case Report Forms (CRFs), ensuring all fields are completed 
appropriately, and all corrections are done according to GCPs.  Any inconsistencies/deviations will be 
documented on the CRFs and such findings will be reviewed at the weekly study meetings. 
 
The Project Manager will oversee staff training.  Training will include a review of the study protocol, informed 
consent, telephone screen, CRFs and the procedures that are in place regarding session check-in, data 
collection, data entry and quality control.   All applicable regulations will be reviewed and the roles/responsibilities 
of each staff member will be explained.   All questions will be answered and the training will be documented in a 
training log, which will be initialed by those involved.  The Project Manager will also confirm all appropriate 
documentation of informed consent and storage of consents in a separate consent binder, and will maintain the 
study regulatory binder. 
 
The Project Manager, PI (Dr. Ashare) and Study Physician will work together to confirm eligibility criteria. The 
Study Physician and PI (Dr. Ashare) will review charts for each subject on an ongoing basis and will document 
reviews by initialing and dating each chart, case report forms that contain blood pressure and heart rate 
measurements, and the medical history and physical form.  
 
The research staff and Project Manager will ensure all medication is properly ordered and received from IDS, 
stored at the center, labeled, and distributed to subjects.   
 
Anita Hole, Ph.D. is responsible for both staff training and continuing review of completed MINI and C-SSRS 
interviews. 
 
The data managers will be responsible for creating all CRFs and ensuring that all data will be entered and stored 
in a manner consistent with the design of the approved CRFs. They will also be responsible for developing the 
data entry/quality control producers for this study. 
 
Enrollment will be complete when 50 subjects complete all study requirements.  On average, 2-3 subjects will be 
enrolled per month. During the course of the study, safety and data quality monitoring will be performed on an 
ongoing basis in accordance with the University of Pennsylvania Sponsor-Investigator Standard Operating 
Procedure PM 504 and any findings will be reviewed on a regular basis with the Investigators at the regular study 
meeting. The monitoring will include a regular assessment of the number and type of serious adverse events. The 
first monitoring day will occur no more than two weeks after the first subject is entered. 
 


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4.2 Adverse Event Reporting and Monitoring 
 
Adverse Event (AE) 
An Adverse Event (AE) is a subcategory of the broader category of "Unanticipated Problems Posing Risk to 
Subject or Others." An adverse event is defined as: 
 
 
Any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease occurring 
at any stage of the study 
 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 
results in study withdrawal 
 
is associated with a serious adverse event 
 
is associated with clinical signs or symptoms  
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
May include an exacerbation of a pre-existing condition, intercurrent illness or injury, drug interaction, drug 
overdose, failure of expected action or significant worsening of the disease under study 
 
An event that may compromise the rights, safety, or welfare of research subjects 
 
Any event that could be characterized by the definitions above is an AE whether or not considered related to the 
study or product. 
 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance. They may jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious. 
 
All adverse events that do not meet any of the criteria for serious will be regarded as non-serious adverse 
events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is the period from the initiation of any study 
procedures to the end of the study treatment follow-up.  For this study, the study treatment follow-up is defined as 
7 days following the last administration of study treatment. A compilation of any Adverse Events will be provided 
in the annual and final progress reports to NIDA.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition will be recorded as 
an adverse event if the frequency, intensity, or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition.  At the end of the 
study, any new clinically significant findings/abnormalities that meet the definition of an adverse event must also 
be recorded and documented as an adverse event.  
 


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Post-study Adverse Event 
All unresolved adverse events will be followed by the investigators until the events are resolved, the subject is lost 
to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, a research team member 
will instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented and reported as 
a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition responsible for 
surgery should be documented as an adverse event if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in 
the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition.  Surgery will not be reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious.  Other kinds of events can be 
labeled “serious adverse events” at the discretion of the investigator.   
 
To ensure no confusion or misunderstanding of the difference between the terms "serious" and "severe," which 
are not synonymous, the following note of clarification is provided: The term "severe" is often used to describe the 
intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations.  
 
Severity Grading Scale for Adverse Events  
Many disease specific groups have developed toxicity grading scales. For example, most cancer clinical trials use 
the Common Terminology Criteria for Adverse Events (CTCAE) developed by the NCI. The CTCAE provides a 
descriptive terminology which is utilized for adverse event reporting. A grading (severity) scale is provided for 
each adverse event term (http://ctep.info.nih.gov ). If no guidelines exist, then the following scale can be used:  
• Mild:  Noticeable to the subject, does not interfere with the subject’s daily activities, usually does not require 
additional therapy, dose reduction, or discontinuation of the study.  
• Moderate:  Interferes with the subject’s daily activities, possibly requires additional therapy, but does not require 
discontinuation of the study.   
• Severe:  Severely limits the subject’s daily activities and may require discontinuation of the study.   This would 
include all adverse events defined as “serious adverse events”.  
 
Attribution/Association with the Drug or Intervention:   
An assessment of the relationship between the adverse event and the drug/intervention will be made for each 
occurrence by the Principal Investigator.   
 
Adverse Event Attribution Categories:  
• Unrelated - The AE is clearly NOT related to the intervention  
• Unlikely - The AE is doubtfully related to the intervention  
• Possible - The AE may be related to the intervention  


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• Probable - The AE is likely related to the intervention  
• Definite - The AE is clearly related to the intervention 
 
4.3 Recording of Adverse Events 
At each contact with the subject after the Intake, the study research assistant will seek information on adverse 
events by specific questioning using a side effect checklist and, as appropriate, by examination. Side effects will 
be monitored through a two-pronged approach. First, participants will complete a side effects checklist (SEC) at 
each study visit after the Intake reporting with a frame of reference since their last study visit. The SEC will assess 
the frequency and severity of common side-effects associated with ramelteon or TN treatment. These items will 
be rated by participants on a 0 (none) to 3 (severe) scale, and can be summed to provide an overall side effects 
index.   
 
Second, trained staff will ask participants a non-structured, open-ended question (SEC Open-ended) at each 
study visit with a one week frame of reference to assess if participants are experiencing any additional symptoms 
or medical concerns that may be related to their participation in the study. 
 
Research staff are trained to inquire (time of onset, nature of issue reported, possible relation to ramelteon/TN 
treatment, review of previously reported side effects or concerns, etc.) about any notable side effects or medical 
concern reported by participants.  Any severe (or a pattern of moderate) side effects or notable medical concern 
will be reported to the Project Manager, Study Physician, and Principal Investigator to determine a course of 
action (e.g. continue to monitor, reduce medication, stop medication).  This consult, including all relevant 
information, will be documented via email. The Study Physician is knowledgeable of side effects related to 
ramelteon/TN and is qualified to manage possible side effects. 
 
Based on published reports using the 8mg dose of ramelteon and 21mg dose of TN we expect few side effects 
and we expect these side effects to be mild and transient in nature. However, in the unlikely event of an adverse 
event (AE) the study physician will determine the severity of the AE, the relationship of the event to the study drug 
and decide the course of action for the study subject. The study physician will determine the relationship of 
toxicity of the study medication as not related, possibly related, probably related, or definitely related using 
standard criteria.  
 
All adverse events occurring during each study period will be recorded. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or participation is 
not the cause. Serious adverse events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation will be recorded and reported immediately. 
 
4.4 Reporting of Serious Adverse Events and Unanticipated Problems 
The following information about adverse events will be reported:   
 
Study Identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association between the event and study treatment 
  Welfare of subjects. 
 
4.5 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, affiliated with a 
Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The University of Pennsylvania 
IRB (Penn IRB) requires expedited reporting of those events related to study participation that are unforeseen and 


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indicate that participants or others are at increased risk of harm.  The Penn IRB will not acknowledge safety 
reports or bulk adverse event submissions that do not meet the criteria outlined below.  The Penn IRB requires 
researchers to submit reports of the following problems within 10 working days from the time the investigator 
becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) that 
occurs any time during or after the research study, which in the opinion of the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected in the 
protocol-related documents, such as the IRB-approved research protocol, any applicable investigator 
brochure, and the current IRB-approved informed consent document and other relevant sources of 
information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in the opinion of the 
principal investigator or sponsor, the event was more likely than not to be caused by the research 
procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn IRB using 
the form: “Unanticipated Problems Posing Risks to Subjects or Others Including Reportable Adverse Events” or 
as a written report of the event (including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other study documentation). 
 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s 
study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the more rapid 
reporting requirement of the Penn IRB for specific situations: 
 Report the event within 24 hours when the death is unforeseen (unexpected) and indicates participants or 
others are at increased risk of harm. 
 Report the event within 72 hours, for all other deaths, regardless of whether the death is related to study 
participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting the IRB Director or 
Associate Director. The AE/Unanticipated Problem Form is required as a follow up to the initial submission. 
 
Reporting SAEs  
• Penn Subjects (including subjects at networks, affiliates or investigator-initiated sites);   
All on-site grade 3 or higher AEs or ADRs regardless of attribution or expectedness will be submitted to the IRB 
within 30 days.  SAEs or SADRs for Penn subjects regardless of attribution or expectedness will be submitted to 
the IRB within 10 days. Reports will continue to be sent to the IRB for 90 days following the last date the subject 
received study treatment/therapy or was exposed to an investigational device.  All unexpected deaths or deaths 
related to the study agent(s)/device(s) must be reported within 24 hours. All other deaths should be reported 
within 30 days.   
 
Other Reportable events: 
- 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
- 
Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse 
event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-
Johnson syndrome). 
- 
Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human subjects. 


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- 
Information that indicates a change to the risks or potential benefits of the research, in terms of severity or 
frequency. For example:  
o An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
o Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
o A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
o Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
o Breach of confidentiality 
o Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
- 
Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the subject to remain in the study. 
- 
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be 
resolved by the research team. 
- 
Exception: A one time, intentional action or process that departs from the IRB and CTSRMC approved 
study protocol, intended for one occurrence. If the action disrupts the study progress, such that the study 
design or outcome (endpoints) may be compromised, or the action compromises the safety and welfare of 
study subjects, advance documented IRB approval is required. 
- 
For exceptions on Industry or Cooperative group sponsored protocols, written approval must be obtained 
from the Sponsor prior to submitting your exception request to the IRB. 
- 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval must 
be obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting your exception 
request to the IRB. 
- 
Deviation: A one time, unintentional action or process that departs from the IRB approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on the protocol 
disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of 
the subjects, the deviation must be reported to the IRB within 10 business days. 
 
Data, Safety and Monitoring Report.  The PI will provide a summary of the DSM report on an annual basis as part 
of the progress report.  The DSM report will include the expected versus actual recruitment rates, treatment 
retention rates, any quality assurance or regulatory issues that occurred during the past year, summary of AEs 
and SAEs, and any actions or changes with respect to the protocol.   
 
Evidence of Training in Human Subject Research.  All research personnel associated with this study have 
completed the CITI-Protection of Human Subjects Research Training as well as HIPAA Compliance Training. 
 
5. Management of Information for Multi-center Research where a Penn Investigator is the Lead 
Investigator of a multi- center study, or Penn is the lead site in a multi-site study.  
Not applicable 
 
Risk/Benefit Assessment 
The importance of this research outweighs the risks to subjects, which are minor. There is minimal risk for serious 
adverse events. The treatments and procedures used in this study have been shown to be relatively safe. 
Numerous clinical trials have demonstrated the safety and efficacy of ramelteon and TN. Research staff will 
monitor subjects closely during their participation. Data from this project will serve as preliminary data to formally 
test ramelteon as an adjunct behavioral component to smoking cessation treatment.   
 
SUBJECT COMPENSATION 
 


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Participants will receive compensation at each session they attend and can receive up to $592 for completing all 
study requirements (including travel reimbursement).  Compensation distribution is shown in the table below. 
 
 
 
 
 
 
 
INFORMED CONSENT 
1. Consent Process 
At the Intake (Day 0), participants will provide written study consent and HIPAA documents (combined) before 
completing additional survey measures and undergoing any study related activities. A member of the research 
staff will explain the study procedures before the start of the Intake visit and ask each participant if they have any 
further questions and provide answers or any clarifications and written consent will be obtained. All individuals 
obtaining consent will have completed the University of Pennsylvania human subject certification and will be fully 
trained in the informed consent process.  Individuals can elect not to participate and may withdraw at any time 
without penalty. Participants will receive a copy of the combined consent/HIPAA form. Hard copies of Intake data 
and a copy of the signed combined consent/HIPAA forms will be stored in a subject’s study folder. The original 
signed combined consents/HIPAA will be centrally stored in Regulatory Consent Binders. 
 
2.  Waiver of Authorization 
Not applicable as we will be operating under FDA regulations. 
 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 
1. Research Staff 
The following research staff will be directly involved with the implementation and execution of the current study.   
 
Rebecca Ashare, Ph.D., Principal Investigator 
 
David Dinges, Ph.D., Co-Investigator 
 
Janet Audrain-McGovern, Ph.D., Co-Investigator 
 
Frank Leone, M.D., Study Physician 
 
Paul Wileyto, Ph.D., Statistician 
Study Visit 
Visit 
Compensation 
Travel 
Armband 
Incentive 
Quit 
Incentive 
Total 
Intake* 
$20  
$10  
 
  
$30  
Week 1 Baseline Session (Mon) 
$10 
$10  
 
  
$20 
Week 1 Baseline Session (Wed) 
$10 
$10 
 
  
$20 
Week 1 Baseline Session (Fri) 
$20 
$10  
$16 
  
$46 
Week 2 Quit Assess. (Mon) 
$10 
$10  
 
$10+ 
$30 
Week 2 Quit Assess. (Tues) 
$10 
$10 
 
$10+ 
$30 
Week 2 Quit Assess. (Wed) 
$10 
$10  
 
$10+ 
$30 
Week 2 Quit Assess. (Thurs) 
$10 
$10 
 
$10+ 
$30 
Week 2 Quit Assess. (Fri) 
$10 
$10  
$20 
$10+ 
$50 
Week 5 Baseline Session (Mon) 
$10 
$10  
 
 
$20 
Week 5 Baseline Session (Wed) 
$10 
$10  
 
 
$20 
Week 5 Baseline Session (Fri) 
$20 
$10  
$16 
 
$46 
Week 6 Quit Assess. (Mon) 
$10 
$10 
 
$10+ 
$30 
Week 6 Quit Assess. (Tues) 
$10 
$10 
 
$10+ 
$30 
Week 6 Quit Assess. (Wed) 
$10 
$10 
 
$10+ 
$30 
Week 6 Quit Assess. (Thurs) 
$10 
$10 
 
$10+ 
$30 
Week 6 Quit Assess. (Fri) 
$10 
$10 
$20+$50a 
$10+ 
$100 
TOTAL 
$200 
$170 
$122 
$100 
  
Grand Total: 
$592 
* Participants who test positive for study prohibited drugs will not be eligible to receive visit or travel 
compensation. 
+ Participants will receive $10/day (in cash) for each day of self-reported abstinence that is biochemically-
confirmed 
a  Participants will be provided $4/day for each day they wear the armband and complete the sleep diary plus 
$50 if they provide at least 18 of 22 days of data (85%) 


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 
Susan Ware, B.S. Database Manager 
 
Paul Sanborn, Samples Manager 
 
Molly Ruben, MPH, Project Manager 
 
Anita Hole, Ph.D. MINI review 
 
Leah La Prate, Study Support Staff  
 
Janice Biddle, CRNP, Study Support Staff 
 
Chan To, Study Support Staff 
 
Erin Logue, Study Support Staff 
 
Victoria McLaughlin, Study Support Staff 
 
Zoe Rosoff-Verbit, Study Support Staff 
 
Katrina Serrano, Study Support Staff 
 
Morgan Thompson, Study Support Staff 
 
2. Staff Training 
Dr. Ashare will oversee the development of protocols for laboratory related tasks and training of staff in these 
protocols. Dr. Ashare will be responsible for the development of procedures pertaining to all other study visits and 
implementing and monitoring ongoing staff training procedures accordingly. An initial, intensive training period will 
be implemented followed by quarterly in-service trainings that will be coordinated by Dr. Ashare.  
 
3. Study Facilities 
This project will be conducted at and through the PENN Center for Interdisciplinary Research on Nicotine 
Addiction (CIRNA), which has numerous similar protocols and well-developed procedures for staff training, data 
collection and storage, and study completion. The facilities available for this project include a large conference 
room, individual consulting rooms with computer/internet access, storage rooms, smoking lab, sample collection 
rooms, office space for study personnel, and data management facilities.  


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