Clinical trial NCT03593538
Conditions: Smoking HIV-1-infection
Sponsor: University of Pennsylvania
Start date: 2016-04-01; Completion date: 2020-03-13
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the effects of a medication called metformin (Glucophage®) on smoking behavior. This medication is FDA-approved for treatment of type-2 diabetes. It is being used for research purposes in this study. Participants will be randomized to one of 3 treatment groups: low dose of metformin, high dose of metformin, or placebo.

Detailed description:
There is a need for novel approaches to optimize smoking cessation treatment to help more smokers quit. Mood disturbance and cognitive deficits during nicotine withdrawal may be important treatment targets given their association with smoking relapse. In addition, factors such as HIV-1 infection may exacerbate abstinence effects on mood and cognitive deficits and thus should be measured and controlled for. The investigators hypothesize that the FDA-approved medication, metformin, will attenuate withdrawal-related mood disturbance and cognitive deficits, controlling for HIV status. Using a well-validated abstinence challenge paradigm, the investigators propose a placebo-controlled double-blind parallel arm study with one between-subjects factor of medication (low dose: 500 mg, high dose: 1500 mg, and placebo). Non-treatment seeking smokers (HIV-: n=54; 18 per group) will complete this 23 day study.

Arms: arm 1: Days 1-7: Metformin 500 mg per day; Days 8-14: Metformin 500 mg and 1 Placebo capsule per day; Days 15-23: Metformin 500 mg and 2 Placebo capsules per day arm 2: Days 1-7: Metformin 500 mg per day; Days 8-14: Metformin 1000 mg per day; Days 15-23: Metformin 1500 mg per day arm 3: Days 1-7: 1 Placebo capsule per day; Days 8-14: 2 Placebo capsules per day; Days 15-23: 3 Placebo capsules per day
Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: Metformin capsule intervention 2: Sucrose filler in gel capsules

Protocol documents:
Prot_SAP_000.pdf: 
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Application for Review of Human Research: IRB Protocol Summary 
Biomedical Research 
Version 15: 8/17/2020 
 
IRB# 824504 
 
 
Names of Investigators: 
Name 
Department  (all at UPenn) 
Robert Schnoll, Ph.D., Principal Investigator  
3535 Market Street, Suite 4100,  
Philadelphia, PA 19104     
215-746-7143 
schnoll@pennmedicine.upenn.edu 
Psychiatry 
Rebecca Ashare, Ph.D., Co-I 
Psychiatry 
David Metzger, Ph.D., Co-I 
Psychiatry 
Frank Leone, MD, Study Physician 
Medicine 
 
PROTOCOL TITLE 
1.  Full Title 
Effects of metformin on mood and cognition during nicotine withdrawal 
 
2.  Brief Title 
Effects of metformin during nicotine withdrawal 
 
STUDY SPONSORSHIP 
1.  Funding Sponsor 
PA Department of Health 
 
2.  Primary Sponsor 
University of Pennsylvania 
 
ClinicalTrials.gov IDENTIFIER 
NCT03593538 
 
PROTOCOL ABSTRACT 
There is a need for novel approaches to optimize smoking cessation treatment to help more smokers quit. Mood 
disturbance and cognitive deficits during nicotine withdrawal may be important treatment targets given their association 
with smoking relapse. In addition, factors such as HIV-1 infection may exacerbate abstinence effects on mood and 
cognitive deficits thus increasing the probability of smoking relapse among HIV-infected smokers (HIV+), compared to HIV-
uninfected smokers (HIV-). We hypothesize that the FDA-approved medication, metformin, will attenuate withdrawal-
related mood disturbance and cognitive deficits and we will explore whether HIV status moderates these effects. Using a 
well-validated abstinence challenge paradigm, we propose a placebo-controlled double-blind parallel arm study with one 
between-subjects factor of medication (low dose: 500 mg, high dose: 1500 mg, and placebo). Non-treatment seeking 
smokers (HIV-: n=54; and HIV+: n=30) will complete this 23-day study. After completing a baseline visit, subjects will 
complete 4 additional sessions (days 7, 14, 21, 23) to assess side effects, smoking rate, mood, craving, and withdrawal. 
Cognitive function will also be assessed on days 21 and 23. Subjects will be instructed to refrain from smoking for 24 hours 
prior to the laboratory session on day 23. The primary outcomes are mood and cognitive function during smoking 
abstinence (vs. smoking as usual). Secondary outcomes include smoking behavior (e.g., cigarettes per day, carbon 
monoxide) during the 3-week run-up period. These data will lay the foundation for a larger Phase IIb clinical trial.    
 
 


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OBJECTIVES 
1.  Overall Objectives 
The objective of this proof-of-concept pilot study is to establish feasibility and generate measures of effect size to support 
future research to evaluate metformin as a potential smoking cessation aid and whether HIV status moderates these 
effects. 
2.  Primary Outcome Variable(s)  
The primary outcomes are mood and cognitive function following 24h of smoking abstinence.  
 
3.  Secondary Outcome Variable(s)  
Smoking behavior (e.g., cigarettes per day, carbon monoxide) during the 3-week run-up period.  
 
BACKGROUND 
Tobacco smoking is the leading cause of preventable death worldwide and presents a major public health burden [1, 2].  
In the United States alone, tobacco smoking accounts for over 400,000 deaths per year, yet 17% of adults continue to 
smoke [3, 4]. Although the ability of smokers to quit has been aided by new medications and counseling, over 50% of 
smokers relapse in formal treatment programs within the first week following a quit attempt [5-7] and only 5-10% achieve 
long-term abstinence [8, 9]. In order to identify novel treatments for smoking cessation, a better understanding of the 
mechanisms by which relapse occurs is necessary. Two plausible behaviors to target are negative affect and cognitive 
function. Indeed, in the general population nicotine withdrawal produces increases in negative affect [10-12] and 
disruption of cognitive function [13-16], often within the first 24 h of abstinence [17, 18]. Importantly, withdrawal-related 
negative affect [19, 20] and cognitive impairment [21, 22] predict relapse.  
 
Recent epidemiological evidence suggests that HIV+ smokers lose more life-years due to tobacco use than to HIV infection 
[23]. Tobacco use increases the risk of developing cardiovascular and pulmonary diseases and cancer and can negate the 
beneficial effects of HAART among HIV-infected individuals [24, 25]. Smoking among HIV-infected individuals can 
exacerbate HIV-related symptoms, worsen overall quality of life [26-29], and increase the likelihood of death [30]. 
Between 39%-69% of HIV-infected individuals exhibit deficits in multiple cognitive domains including memory, attention, 
processing speed, verbal fluency, and executive function, known as HIV-associated neurocognitive disorders (HANDs) [31, 
32]. These mild cognitive deficits are associated with functional disabilities including unemployment, difficulty driving, and 
poor adherence to HAART [33-35]. Moreover, rates of psychiatric comorbidity, such as depression, are twice as high 
among HIV-infected individuals, compared to uninfected individuals [36, 37]. Critically, smoking can accelerate the 
incidence and progression of HANDs [38, 39] and HIV+ smokers are more likely to report elevated symptoms of depression 
compared to nonsmokers [40, 41].  Cessation treatments for HIV+ individuals may need to target withdrawal symptoms 
associated with psychiatric comorbidity and cognitive impairment [42]. 
 
Mitigating these features of nicotine withdrawal will require the identification of new targets for the development of novel 
medications or repurposing of existing drugs to treat nicotine dependence. We made the exciting discovery in mice that 
chronic nicotine exposure causes robust phosphorylation of AMPK (AMP-activated protein kinase), which is reversed upon 
nicotine withdrawal. We found that by increasing pAMPK using the FDA approved drug metformin, we could reduce 
anxiety-like behavior and cognitive deficits following nicotine withdrawal in mice. This new target is particularly exciting, 
as it suggests that metformin, the widely used diabetes medication, could be repurposed to provide a novel treatment for 
nicotine addiction by attenuating negative affect and cognitive deficits during a quit attempt. Indeed, evidence suggests 
that metformin (vs. placebo) improves cognitive performance and reduces symptoms of depression among depressed 
patients with type-2 diabetes [43]. Among older adults with diabetes, metformin may attenuate cognitive decline [44]. 
Moreover, AMPK is a key metabolic regulator that senses the energy status of the cell and regulates fuel availability [45, 
46] and recent evidence suggests that smoking cessation is associated with increased risk for metabolic syndrome [47]. A 
recent study reported increased diabetes and impaired fasting glucose three years following a quit attempt [48] and insulin 
resistance caused by smoking persists for two years following cessation [49]. Therefore, therapy that addresses not only 
the symptoms associated with nicotine withdrawal but also another leading cause of preventable disease, i.e. type 2 
diabetes [50], would be of great benefit. 


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We hypothesize that because HIV-infected individuals are more likely to experience mood disturbance [36, 37] and 
cognitive dysfunction [38, 39], MET (vs. placebo) will attenuate increases in mood disturbance and cognitive dysfunction 
(verbal and working memory, executive function, and response inhibition) following 24 hours of smoking abstinence 
among HIV-infected smokers. We will also test whether MET (vs. placebo) reduces smoking behavior (e.g., cigarettes per 
day, carbon monoxide) during the 3-week drug run-up. Lastly, we will explore whether there is an added benefit to 
increasing the dose to 1500 mg (vs. 500 mg) without corresponding adverse effects. The proposed study is uniquely 
positioned to identify a potential new smoking cessation treatment for a population of smokers with high smoking relapse 
rates. 
 
CHARACTERISTICS OF THE STUDY POPULATION 
1. Target Population 
Adult, non-treatment seeking smokers (HIV-: n=54; and HIV+: n=30), 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. HIV-infected smokers 
have been diagnosed with HIV/AIDS (identified through the UPENN CFAR Clinical Core, UPHS PennChart reviews and 
community-based HIV/AIDS organizations and events; see specific criteria below) and HIV-uninfected smokers will have 
no diagnosis of HIV, either via blood test (see recruitment strategy below) or self-report. 
 
2.  Accrual 
One hundred and sixty HIV- and ninety HIV+ subjects will be enrolled in order to have 54 HIV- and 30 HIV+ smokers complete 
all sessions, accounting conservatively for 30% attrition. 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 one of the three groups: 
low dose (500 mg), high dose (1500 mg), or placebo.  
 
3.  Key Inclusion Criteria  
Eligible subjects will be males and females: 
1. 18 years of age or older who self-report smoking at least 5 cigarettes (menthol and non-menthol) per day, on 
average for the past 6 months. 
2. HIV status 
a) HIV-infected smokers: diagnosed with HIV infection and exhibiting viral load of less than or equal to 
1000 copies/mL and CD4+ counts of greater than or equal to 200 cells/mm3 within 6 months prior to 
enrollment. 
b) HIV-uninfected smokers: no diagnosis of HIV, either via blood test or self-report. 
3. Must not currently be interested in quitting smoking.  
4. Women of childbearing potential (based on medical history) must consent to use a medically accepted method 
of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, 
tubal ligation) or abstain from sexual intercourse during the time they are in the study and using transdermal 
nicotine. 
5. If current or past diagnosis of bipolar disorder, eligible if:  
a. No psychotic features 
b. MADRS: total score less than 8 (past 4 weeks), suicidal item score less than 1 (past 4 weeks) 
c. Y-MRS: total score less than 8 (past 4 weeks), irritability, speech content, disruptive or aggressive behavior 
items score less than 3 (past 4 weeks) 
d. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in the past 6 months  
e. No aggressive or violent acts or behavior in the past 6 months 
6. Able to communicate fluently in English. 
7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions 
listed in the combined consent/HIPAA form. 
 
 


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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. 
 
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. Current untreated and unstable diagnosis of substance dependence (eligible if past use and if receiving treatment 
and stable for at least 30 days). Current untreated and unstable diagnosis of substance abuse requires Study 
Physician approval.  
3. A positive urine drug screen for cocaine, amphetamines, methamphetamines, PCP, barbiturates and ecstasy 
(MDMA) at Intake, or any testing session (see Measures and Table 1 for details). Participants believed to have a 
false-positive result may continue in the study, with investigator approval. 
 
Medical:   
1. Females who self-report current pregnancy, planning a pregnancy during the study, or currently 
breastfeeding/lactating. All female subjects of child-bearing potential shall undergo a urine pregnancy test at the 
Intake, Baseline, PQ-Testing and 24-H Testing sessions.  
2. Current diagnosis of unstable and untreated major depression, as determined by self-report & MINI (eligible if 
stable for at least 30 days). 
3. Current or past diagnosis of psychotic disorder, as determined by self-report or MINI. 
4. Suicide risk as indicated by at least one of the following on the MINI/CSSRS (the PI &/or PM (LCSW) will be 
consulted to assess safety and determine eligibility in cases close to the eligibility cutoffs): 
a. Current suicidal ideation (within 30 days of enrollment) 
b. Two or more lifetime suicide attempts or episodes of suicidal behavior 
c. Any suicide attempt or suicidal behavior within 2 years of enrollment 
5. Self-reported kidney and/or liver disease or transplant untreated/unstable or within the past 6 months. 
6. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in the past 6 months. 
7. Type-1 or type-2 diabetes. 
8. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than 99)*. 
9. Liver function tests more than 20% outside of the normal range; 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 determined on 
a case-by-case basis. 
10. Renal disease or renal dysfunction (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females]). 
11. A blood glucose level less than 70 mg/dl at any visit. 
 
* 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 ineligible to participate, unless determined otherwise by the Study PI/Co-I or Study Physician, upon 
review. 
 
Medication:   
1. Current use or recent discontinuation (within the past 14 days) of any of the following medications: 
a. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam). 
b. Anti-psychotic medications as assessed on a case-by-case basis 
c. Glucophage/metformin 
d. Glyburide 
e. Furosemide or digoxin 
f. Nifedipine 


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g. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, 
triamterene, trimethoprim, or vancomycin) 
2. Participants who report taking prescription opiate-containing medications (Duragesic/fentanyl patches, Percocet, 
Oxycontin) will require physician approval prior to confirming final eligibility.  
3. Current use of any smoking cessation medications (e.g., Chantix/varenicline, Zyban/bupropion, nicotine 
replacement therapy/gum/patch). 
4. For safety reasons, HIV-infected smokers taking dolutegravir (Tivicay) or drugs that contain dolutegravir (e.g., 
Triumeq) should not take more than 1000 mg of metformin per day. Therefore, individuals taking dolutegravir will 
be force randomized to either the placebo condition or the low dose condition. 
 
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. Color blindness. 
4. Any impairment (physical and/or neurological) including visual or other impairment preventing cognitive task 
performance. 
5. 
Known allergy to study medication. 
6. Planned radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous 
urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular 
contrast materials) during the course of study participation. 
7. Inability to provide informed consent or complete any of the study tasks as determined by the Principal 
Investigator. 
8. Not able to effectively communicate in English (reading, writing, speaking). 
9. Missing 3 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 
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 several 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 advertising (i.e., Craigslist, flyers, newspaper or TV ads) will be used to invite smokers from the general 
population. 
 
Participants will be recruited from the Infectious Disease practices at the Hospital of the UPENN, Presbyterian Hospital, 
and Pennsylvania Hospital. The PMHARC will oversee the integration of this study into the clinics, ensuring access to 


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participants, collection of medical data (through UPHS PennChart medical record reviews and laboratory result requests), 
and access to private consulting rooms for screening at the clinics. These practices see over 500 patients monthly and 
more than 200 new patients each year.  
 
After obtaining the necessary training and clinic clearances to access PennChart for participating UPHS clinics, Research 
Assistants (RAs) will review the electronic medical records to identify potential subjects on a weekly basis (each site has 
patient smoking status indicated on the record). Individual medical records will be evaluated for eligibility based on the 
inclusion and exclusion criteria for this study. Daily clinic schedules will be ascertained and RAs will approach patients prior 
to or after consultation or treatment at the clinic. In addition to in-clinic recruitment, RAs will contact potentially eligible 
patients (after EMR review) by telephone based on their clinic provider’s specified research contact preference. Providers 
may choose one of the following contact options: 1) all patients identified as initially eligible may be contacted 2) all 
patient records identified as initially eligible will be sent to the provider via PennChart for review and approval prior to 
contact 3) all patient records identified as initially eligible may be sent to the provider, who assumes full responsibility and 
discretion regarding the research contact (no contact may be made by the research staff). Those patients deemed eligible 
for contact will be contacted by telephone. RAs will introduce the research study and the collaboration between the 
researchers, infectious disease clinic, and the patient’s provider. After assessing the patient’s interest, HIV status, and 
smoking status, the patient will then be provided with additional study information and an opportunity to assess his/her 
intake eligibility based on a screening questionnaire. 
 
If our accrual rate is lower than anticipated based on our feasibility data, Dr. Metzger and the PMHARC Clinical Assessment 
Core (CAC) will use their connections with community-based HIV/AIDS organizations in the Delaware Valley region to 
promote the trial and enhance accrual rates. The PMHARC CAC, comprised of people with HIV/AIDS or professionals in 
the treatment of substance use among those with HIV, has numerous linkages to community-based organizations that can 
be used to enhance participant recruitment should that be necessary. We will also advertise the study using poster, 
newspaper, and internet-based advertisements (this includes in-app advertising, Craigslist, and Twitter). Information 
about the study will be available on the CIRNA and iConnect websites. In addition, research staff will attend HIV/AIDS 
community events and community clinic intake hours to provide information about the study, distribute recruitment 
materials, and collect participant contact information via a secure, web-based data collection service. Additionally, we will 
place recruitment data requests with electronic research data warehouses such as Penn Data Store, PennOmics, and 
PennSeek to obtain lists of pre-consented potential participants. ResearchMatch, a national health volunteer registry that 
was created by several academic institutions and supported by the U.S. National Institutes of Health as part of the Clinical 
Translational Science Award (CTSA) program, will also be utilized. ResearchMatch has a large population of volunteers 
who have consented to be contacted by researchers about health studies for which they may be eligible.  
 
RAs and UPHS medical personnel will screen patients from UPENN and community-based HIV/AIDS clinics to identify 
potentially eligible and interested participants by phone or in person. Participants recruited through other methods will 
also be screened by phone or in person. Participants who are eligible and interested in the study will complete the Intake 
session (Week 0) with research staff. The participant will review and sign an informed consent and HIPAA form, complete 
eligibility and baseline assessments, and be scheduled for a Week 1 visit. The participant’s eligibility will be confirmed by 
Drs. Leone and Ashare. 
 
To ensure a high level of retention and adherence in this trial we will: 1) educate subjects about the benefits of protocol 
compliance; 2) schedule in-person sessions at convenient times (e.g., evenings); and 3) provide modest financial 
compensation for session completion and transportation costs.    
 
Referral Bonus Program 
Participants who achieve their final study visit (Day 23) will be given the opportunity to receive a small bonus for referring 
others to the program. If the person who is referred completes the initial eligibility phone screen, regardless of outcome, 
the study participant will be awarded $20 per referral, for a maximum of 3 referrals ($60). 
 


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STUDY DESIGN 
1.  Phase 
N/A 
 
2. Design 
We propose to conduct a randomized, placebo-controlled, parallel arm study with one between-subjects factor of 
medication (low dose, high dose, placebo). Once eligibility is confirmed after Intake, subjects will attend a clinic visit (day 
0) to establish baseline smoking rate, mood, and cognition. Subjects will then be randomized to one of three groups (low 
dose: 500 mg, high dose: 1500 mg, or placebo) and will complete 4 additional sessions (days 7, 14, 21, 23) to assess side 
effects, smoking rate, mood, craving, and withdrawal (Figure 1). Cognitive function will also be assessed on days 21 and 
23. Subjects will be instructed to refrain from smoking for 24 hours prior to the laboratory session on day 23 (Figure 1). 
Following FDA guidelines, the dosing regimen for metformin extended release (XR) will be 500 mg q.d for the low dose. 
For the high dose, the dosing regimen will be: 500 mg q.d (days 1-7); 1000 mg q.d (days 8-14); 1500 mg q.d (days 15-23). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Study Duration  
Estimated length of time to enroll all subjects and complete the study 
Enrollment will start in March 2016. We estimate that we will need to telephone screen 660 smokers to enroll 160 HIV- 
smokers into the study. We expect a drop-out rate of 30% based on prior experience and expect to have 54 HIV- smokers 
complete the study. In addition, we will telephone screen 400 HIV+ smokers to enroll 90 and have 30 HIV+ smokers 
complete the study. 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 4 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 baseline visit. 
Thus, the maximum duration a participant can be in the study is 10 weeks. Additionally, subjects may be contacted after 
study participation to clarify self-report data collected during their active participation, if necessary for data analysis. 
 
Projected date of completion of the proposed study  
We estimate that 54 HIV- and 30 HIV+ smokers will have completed the study by January 2021, and that analyses and 
reporting will be complete by April 2021. 
 


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DRUGS OR DEVICES 
Metformin 
The study will be performed using metformin, which is currently marketed for the treatment of type 2 diabetes mellitus.  
 
The proposed study follows the typical dosing regimen for metformin for both the low and high dose groups. The dosing 
regimen for metformin extended release (XR) will be 500 mg q.d for the low dose. For the high dose, the dosing regimen 
will be: 500 mg q.d (days 1-7); 1000 mg q.d (days 8-14); 1500 mg q.d (days 15-23). This dosing regimen is documented to 
be safe and well-tolerated in prior clinical studies with no gender or age effects on its pharmacokinetics [51, 52]. 
Participants will be instructed to take the study medication once daily with their evening meal. Metformin will be 
purchased and packaged into blister packs by the Investigational Drug Service at the University of Pennsylvania.  
 
An IND exemption has been granted for this study 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 
 
Metformin will be purchased and supplied via the University of Pennsylvania Investigational Drug Service (P1377). 
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. Metformin 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). 
 
Once the Study Physician (Dr. Leone) or Nurse Practitioner signs the prescription, medication kits will be ordered and 
picked up from IDS by a member of the research staff. These kits will be stored in a locked cabinet at our center. 
Medication will be stored at CIRNA as per manufacturer’s guidelines. If needed, staff may request that IDS ship the study 
medication directly to a subject. IDS will oversee the randomization of subjects to a medication group based on sex, and 
will label each kit with the subject’s study ID number and PRN. The PRN and study ID number must match for each blister 
pack a subject receives. Each medication kit will consist of 23 days of metformin or placebo (see above for dosing 
guidelines). To maintain double-blind procedures, all groups will take the same number of pills each day. For example, 
when the high dose group reaches the 1500 mg dose they will take 3 active pills containing 500 mg each of metformin, 
the low dose group will take 1 active pill containing 500 mg metformin and 2 placebo pills each day, and the placebo group 
will take 3 placebo pills.  
 
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. 
 
SUICIDAL IDEATION 
The C-SSRS will be administered remotely (via phone or videoconferencing) as part of 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. In addition, the CES-D will be administered at follow-up visits to monitor changes in depressive symptoms 
throughout the trial. 


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STUDY PROCEDURES 
1.  Procedures 
This is a randomized, double-blind placebo-controlled, parallel arm pilot study of the effects of a low vs. high dose of 
metformin on abstinence-induced negative mood and cognitive deficits. Participants will complete Intake tasks to 
determine final eligibility before being enrolled into the study. Study visits will be completed either in-person at our center, 
or remotely (via phone or videoconferencing). Once eligibility is confirmed, subjects will attend a clinic visit (day 0) to 
establish baseline smoking rate, mood, and cognition. Subjects will then be randomized to one of three groups (low dose: 
500 mg, high dose: 1500 mg, or placebo) and will complete 4 additional sessions (days 7, 14, 21, 23) to assess side effects, 
smoking rate, mood, craving, and withdrawal (Figure 1). Cognitive function will also be assessed on days 21 and 23. 
Subjects will be instructed to refrain from smoking for 24 hours prior to the laboratory session on day 23.  
 
2. Study Visits 
• 
Telephone Screening. Recruited subjects will complete an initial eligibility assessment in the HIV/AIDS clinic or over 
the telephone. This assessment reduces the likelihood that participants attend an Intake Session only to learn that 
they are ineligible or to allow us to ascertain physician’s clearance should the participants have a medical condition 
that requires approval (e.g., mild hypertension). If a potential participant cannot be reached by phone, staff may send 
a text for the purposes of scheduling an initial eligibility screening phone call. This will help to reach potential 
participants who express interest in the study but do not answer phone calls from unrecognized numbers or do not 
regularly listen to voicemail messages. Texts will be sent from a central study account and not from the personal 
cellphones of any research staff. Participants who are initially eligible will be screened against our registration 
database to confirm that they are not currently participating in another research study at our Center and have not 
previously reported a condition or circumstance that would make them ineligible for the current study. Those 
participants who remain initially eligible will move forward with elegibility-determining tasks as part of the Intake 
session, which will be completed remotely and in-person. The Intake session must occur within 60 days of the initial 
eligibility screening or the participant will have to be re-screened. 
 
• 
Visit Reminders. Subjects will be contacted via phone call, text message, e-mail and/or postal mail to remind them 
about their scheduled sessions. Subjects will be asked to indicate their preference after screening. 
 
• 
Remote Study Participation. If needed, study sessions may be carried out remotely, including some Intake tasks. This 
enables us to continue collection of data in a rigorous way while maintaining the safety of subjects. Additionally, if a 
participant is unable to attend an in-person visit, either due to personal reasons or office closure, procedures will be 
modified to allow for remote collection of data. The procedure for visit reminders will remain the same. Participants 
will be contacted via call or text to remind them of the time of their session, as well as to remind them that the session 
will be conducted by phone. Staff will call participants to complete all measures that can be completed by phone. If 
collected on-site using session paperwork, these data will be stored in the participants’ charts and locked in secure 
filing cabinets, as is standard procedure. In the event that research staff are off-site, paperwork will be completed via 
RedCap. If RedCap is unavailable, they will utilize Pulse Secure to enable a secure, remote connection to their desktops 
and the secure server. Data collected remotely will be stored on our secure server, and later transcribed to paper 
measures and stored in participant charts or entered into RedCap. Items that are typically dispensed to participants 
at certain visits may be shipped to the participant, including study medication and a ClinCard, for payment purposes. 
 
• 
Intake (Day -1). Participants who pass the pre-screening will be asked to complete tasks to determine their eligibility 
for the study. Tasks 1-5 listed below may be completed remotely by phone or videoconference using BlueJeans 
(HIPAA-compliant), to reduce the length of in-person tasks. If remote, measures will be administered using RedCap 
surveys. The tasks may take up to 2.5-hours if completed entirely in-person. Subjects will be asked to: 
1. Complete the consenting process remotely (per procedure outlined in the Informed Consent section) or in-
person. Staff will review the consent form and answer all questions. Staff will then administer a 
comprehension questionnaire and review incorrect answers as needed. If completed remotely, subjects who 
are unable to provide an electronic signature may be mailed a physical version of the consent that must be 
signed and returned to us prior to continuing with the Intake tasks. 
2. Complete mental status exams (MINI and C-SSRS and MADRS, YMRS, Bipolar Disorder Additional Screener, if 
necessary) with trained research staff member. 


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3. Complete routine medical history (self-report), including concomitant medication review with a member of 
the research staff. 
4. Complete the Shipley Institute of Living Scale 
5. Complete baseline measures 
6. Provide urine specimens for drug and (if applicable) pregnancy tests. Participants who test positive for either 
the urine drug screen and/or pregnancy test may be ineligible. Participants believed to have a false-positive 
result may continue in the study, with investigator approval. 
7. Provide a CO breath sample. 
8. Complete physiological measures such as blood pressure, height and weight. 
9. Complete brief physical examination (led by a medical professional). If the provider is off-site this will be 
conducted via telehealth. 
10. Provide an 8.5ml blood sample drawn for the assessment of liver function (LFTs and GGT enzyme levels) and 
creatinine levels. They will receive final confirmation of eligibility via phone call based on the blood test results. 
 
If a participant meets the above eligibility criteria at the Intake, they will finalize their study schedule with staff. 
 
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.  
 
• 
Final Eligibility Phone Call.  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 and serum creatinine levels less than 1.5 mg/dL [males], less than 1.4 mg/dL [females]). 
Albumin/Globulin ratios 20% outside of normal range will be evaluated for clinical significance by the Study Physician 
and eligibility will determined on a case-by-case basis. 
 
Eligible subjects will confirm the study schedule and be randomized to a medication group. Ineligible subjects may be 
referred to other studies at our center.   
 
• 
Baseline Session (Day 0).  Participants will complete a 1.5-hour Baseline session before starting study medication.  The 
Baseline session must be scheduled at least 2 days after Intake, but no more than 30 days can elapse between Intake 
and Baseline.  At the Baseline session participants will: 
1. Provide a CO sample. 
2. Provide urine specimens for drug and (if applicable) pregnancy tests.  Participants who test positive for the 
urine drug screen may be withdrawn from the study. Participants believed to have a false-positive result may 
continue in the study, with investigator approval. 
3. Complete a blood pressure measurement (See Blood Pressure Procedures under Screening/covariate 
measures). 
4. Have their blood glucose measured via a handheld glucose monitoring test (see Measures: 
Screening/Covariates). Subjects who have a low blood glucose level (i.e., less than 70 mg/dl) will be provided 
a beverage containing at least 15 g carbohydrates (e.g., 4 oz of fruit juice). 
5. Provide two 10 ml and 2 8.5 ml blood samples (less than 3 tablespoons) for examining biomarkers of 
neuroinflammation (HIV+ subjects only). 
6. Complete questionnaires (smoking rate, concomitant medication review, withdrawal, smoking urges, mood, 
subjective effects, and side effects). * 
7. MADRS, YMRS, Bipolar Disorder Additional Screener, if necessary* 
8. Complete cognitive tasks which may include tasks assessing working memory (n-back), verbal learning 
memory (HVLT-R), cognitive flexibility (color shape task), response inhibition (stop-signal task), and delay 
discounting. 


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9. Be given instructions for study medication. Medication may be mailed to the participant or provided at the 
session. 
 
 
* Some tasks may be completed remotely to reduce the length of in-person visits. 
 
This session can be scheduled any time of day. However, the timing of this session will influence when the Day 21 
and Day 23 testing appointments are scheduled. Ideally, the subsequent testing sessions would be at the same 
time of day but can be scheduled up to 3 hours earlier or later than the Baseline session. However, the sessions 
may go beyond 3 hours as determined by PI/Co-I discretion. 
 
• 
Remote Check-In(Days 7 and 14). These sessions will be completed remotely via phone or videoconference and will 
last about 20 minutes. Participants will be asked to: 
 
1. Report their smoking rate (timeline followback; TLFB)  
2. Report their medication adherence 
3. Report side effects and complete a concomitant medication review 
4. Complete measures for mood, smoking urges, withdrawal symptoms, and subjective effects 
5. Complete the MADRS, YMRS, Bipolar Disorder Additional Screener, if necessary 
6. Review instructions for medication 
 
This visit can be scheduled any time during the day and can be moved by plus or minus 1 day to accommodate for 
participant’s schedule. 
 
• 
Pre-Quit Testing Day (Day 21). Participants will be asked to bring their study medication to this visit. During this 2-hour 
visit, participants will complete the same activities they completed at the Baseline Session except that they will 
complete additional measures of pill count.  
 
• 
Mandatory 24-H Abstinence Period. On Day 22, participants will receive a telephone call to remind them to begin their 
practice quit attempt approximately 24 hours before their scheduled 24-H testing session on Day 23. Participants will 
also be reminded that in order to remain eligible for the study, they must remain abstinent during this 24-hour period. 
 
• 
24-H Testing Day (Day 23). The 24-H Testing Day occurs after approximately 24 hours of abstinence from nicotine. The 
Testing Day Visit takes about 2 hours to complete and is split into two parts. The procedures participants will complete 
within each part of the Testing Day Visit are as follows: 
• 
24-H Testing Day Part 1 
On Day 23 Part 1, participants will provide: 
1. A CO sample to verify abstinence. Mandatory abstinence will be biochemically confirmed by a CO 
reading of less than or equal to 8 ppm. If the CO reading is not less than 9 ppm, but there is a 50% 
reduction from the CO collected at the Baseline Visit, this will be considered sufficient and the 
participant may continue as scheduled. If neither condition is met, but participant reports abstinence, 
investigator approval will be needed for participant to continue with the session. If a participant 
smokes (self-reported or biochemically confirmed) during the mandatory abstinence period, they may 
be withdrawn from the study.  
2. A urine sample for a urine drug screen and (if applicable) pregnancy test. If urine drug screen is 
positive, participants may be withdrawn from the study. Participants believed to have a false-positive 
result may continue in the study, with investigator approval. 
3. Blood pressure (See Blood Pressure Procedures under Screening/covariate measures) 
4. Have their blood glucose measured via a handheld glucose monitoring test (see Measures: 
Screening/Covariates). Subjects who have a low blood glucose level (i.e., less than 70 mg/dl) will be 
provided a beverage containing at least 15 g carbohydrates (e.g., 4 oz of fruit juice). 
5. Report their medication adherence/review pill count* 
6. Report side effects and concomitant medication review* 
7. Complete questionnaires (mood, smoking urges, attention, and withdrawal symptoms) * 


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8. MADRS, YMRS, Bipolar Disorder Additional Screener, if necessary* 
9. Complete a cognitive task battery (described below) 
 
• 
24-H Testing Day Part 2 (Programmed Lapse) 
1. Participants will be instructed to smoke one of their own cigarettes in the CIRNA Smoking Laboratory.  
2. Following the programmed lapse, participants will complete the assessments of the subjective and 
rewarding effects of the ‘programmed lapse’ cigarette (Table 1). 
 
 
* Some tasks may be completed remotely to reduce the length of in-person visits. 
 
2.1 Post-Study Follow-up 
If necessary, subjects may be contacted after study participation to clarify self-report data collected during their active 
study participation. Although procedures are in place to ensure data accuracy during active participation, there are 
instances when it may be necessary to conduct a post-study follow-up to maintain data accuracy when analyzing study 
outcomes. If study staff are unable to contact a subject for follow-up, no further action will be taken.  
 
3. Description of Measures and Variables   
 
3.1 Screening/Covariate Measures 
Demographics and Smoking History. Standard questionnaires will be administered remotely or in-person at Intake 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 [53]. The FTND scale has satisfactory internal consistency (Cronbach's alpha=. 64) and high test-retest 
reliability (r=. 88) [54]. 
 
Medical History. A medical history (self-report) and a physical examination will be conducted remotely or in-person at 
Intake to review for any contraindications listed previously. If the NP/provider is off-site, staff will coordinate a telehealth 
visit for the participant while they are at the center, via phone, FaceTime or BlueJeans (both HIPAA-compliant). The 
medical history (including height and weight) will be completed by a research staff member. For the HIV-infected group, 
duration since HIV/AIDS diagnosis, mode of transmission, and viral load and CD4+ counts will be assessed. Current 
medication usage will be tracked at each time-point. 
 
Psychiatric/Substance Use 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 [55]. The MINI will be administered by a trained research staff member remotely or 
in-person as part of the Intake session. There will be 100% review of paper MINIs by the PM, a licensed clinical social 
worker, with relevant training, to maintain quality control. Dr. Ashare, a clinical psychologist, will serve as back-up when 
needed. 
 
Suicidal Behavior and Ideation (C-SSRS). All participants will complete the C-SSRS (Screening Version) with a trained staff 
member remotely or in-person. The C-SSRS is a structured interview that assesses the suicidal behavior and suicidal 
ideation in subjects [56, 57]. 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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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, holding their 
breath for two seconds, releasing the breath, then taking another deep breath and holding 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 in-person study visit. 
 
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, systolic blood 
pressure remains greater than 159 and/or diastolic remains greater than 99, the participant will be ineligible for the study, 
unless determined otherwise by the Study PI/Co-I or Study Physician, upon review.  
 
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 and/or diastolic blood pressure greater than 99) at any subsequent visit, the 
staff will follow the same steps listed above. If, after the second reading, systolic blood pressure remains greater than 159 
and/or diastolic remains greater than 99, the Study Physician or Study PI will be consulted to discuss whether the 
participant should continue taking the study medication. Research staff will follow up with the participant accordingly. 
 
Shipley Institute of Living Scale. All participants will complete the Shipley Institute of Living Scale (SILS) remotely or in-
person as part of the Intake session. The SILS is a self-administered test designed to assess general intellectual functioning 
in adults and adolescents and to aid in identifying cognitive impairments [58]. The scale consists of two subtests, a 40-
item vocabulary test and a 20-item test of abstract thinking. The total administration time is 20 minutes (10 minutes per 
subtest). A trained member of the study staff will score the test. The SILS correlates with the Wechsler Adult Intelligence 
Scale-Revised (WAIS-R) Estimated IQ Test and is considered a highly reliable assessment tool; with a good total score 
internal consistency (Cronbach’s alpha= .92). 
 
Urine Drug Screen. The urine drug screen will be administered at Intake and each testing session (baseline, day 21, and 
day 23). The urine drug screen requires about 30ml of urine and indicates whether the subject has recently taken any 
exclusionary drugs (cocaine, PCP, amphetamines, methamphetamines, ecstasy and barbiturates). Participants with a 
positive urine drug screen for any substance listed above other than THC, opiates, or methadone will be deemed ineligible. 
The rationale for excluding these participants is because one of the primary outcomes in this study is cognitive function. 
Thus, excluding individuals who screen positive for substances that may interfere with their ability to perform the cognitive 
tasks (e.g., benzodiazepines may slow reaction times) reduces this potential source of variability. 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. In addition, the current protocol does not utilize PennChart and therefore, results of the screening will not 
be added to participants’ electronic medical records. 
 
Urine Pregnancy Test. At the Intake and each testing session (Baseline, day 21, and day 23), 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. 
 
Depression and Anxiety. The Hospital Depression and Anxiety Scale (HADS) [59], a 14-item self-report measure, will assess 
depression and anxiety symptoms. This scale correlates with clinical ratings of depression and anxiety [59] and is used 
with HIV-infected individuals [60]. Because depressive symptoms are associated with deficits in cognitive function [61] 
and lower HAART adherence [62], the HADS will be evaluated as a potential moderator of abstinence effects on cognitive 
function and relapse. The HADS will be administered at each visit. 


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Bipolar Disorder Symptoms: If a diagnosis of bipolar disorder is self-reported or revealed via the MINI at Intake, the 
Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and a Bipolar Disorder 
Additional Screener will be completed, remotely or in-person, at all study sessions to evaluate and monitor the presence 
and severity of bipolar disorder symptoms.   
 
Functional Impairment. The Patient’s Assessment of Own Functioning Inventory (PAOFI) will be used to assess cognitive 
difficulties in everyday life. The PAOFI assesses areas such as mental acuity, employment, social functioning, shopping, 
cooking, housekeeping, laundry, driving, use of public transportation, maintaining schedules, medication management, 
financial management, understanding media events, and child care [63]. The degree of functional impairment is used to 
distinguish between categories of HANDs [64]. This measure will be used to evaluate whether those with baseline 
functional impairment, or functional impairment during nicotine withdrawal, have more difficulty maintaining abstinence.  
 
Risk Assessment Battery (RAB). This is a self-report questionnaire designed to assess high-risk behaviors associated with 
HIV transmission. The measure yields two scores: Drug Risk Behavior (e.g. sharing needles, IV drug use) and Sex Risk 
Behavior (e.g., exchanging sex for drugs, unprotected sexual activity). 
 
The BASIS-24.  The BASIS-24 is a 24 item self-report inventory designed to measure mental health status from the patient’s 
point of view. The items cover 6 domains including: depression/functioning, interpersonal relationships, psychotic 
symptoms, alcohol/drug use, and emotional lability. 
 
The SF-12.  This measure is used to assess health-related psychosocial functioning. This well-validated, self-report tool 
measures 8 health-related dimensions: physical functioning, bodily pain, role limitations due to physical health problems, 
role limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and 
general health perceptions. 
 
Quick Inventory of Depressive Symptomatology- Self Report (QIDS). The QIDS is a 16-item self-report measure designed 
to assess the severity of depressive symptoms using the criterion symptoms designated by the DSM-IV. 
 
Liver Function, Gamma-glutamyl Transpepsidase, and Creatinine tests. One 8.5ml blood sample will be drawn at the Intake 
visit. Blood will be collected and placed in a serum-separator tube (SST) and mixed thoroughly.  Samples will be centrifuged 
at 3100 rpm for 10 minutes. If separation is not complete, the sample will be centrifuged at the same RPM for an additional 
5 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) 
10. Creatinine. 
 
Neuroinflammation. Blood samples will be collected at Baseline and Pre-Quit Testing visits to explore the association of 
biomarkers of neuroinflammation using a 6 cytokine assay (e.g., C-Reactive Protein; Interleukin-6) with smoking status 
and cognition (HIV+ group only). Whole blood will be collected in two EDTA tubes and two SST tubes at each visit and 
delivered to the Laboratory Biomarkers, Quantitative Pharmacology, Neuroimaging, and Neurobehavioral 
Characterization Core at the Penn Mental Health AIDS Research Center for storage and analysis.  
 
Blood Glucose. Because metformin may lower blood glucose, glucose levels will be measured at each in-person study 
visit. As recommended by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), blood glucose 
levels in non-diabetic individuals less than 70 mg/dl may indicate hypoglycemia. The Abbott Precision Xtra Blood Glucose 
& Ketone Monitoring System will be used to measure blood glucose 
(https://freestyleserver.com/Payloads/IFU/2017july/ART24315-002_rev-A_WEB.pdf ). This device is indicated for home 


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and professional use. As recommended by the manufacturer, the device will be cleaned and disinfected after each use. A 
trained member of the research staff will obtain a drop of blood (approximately 0.3 microliter) via a finger prick using a 
lancing device. The device provides a blood glucose reading within 60 seconds. Individuals who have a blood glucose 
level less than 70 mg/dl will be provided a beverage containing 15 g of carbohydrate (e.g., fruit juice or soft drink) and 
asked to wait in the laboratory. After 15 minutes, blood glucose will be rechecked to ensure it is greater than 70 mg/dl 
before allowing the participant to leave. Participants who present with blood glucose less than 70 mg/dl may be 
withdrawn from the study. 
 
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. 
 
Side Effects. A checklist of side effects based on the product insert will be administered at all study visits after the Intake. 
Checklists will be reviewed by staff following completion to confirm participant description of any experienced side effect 
matches the severity chosen, based on the severity classifications outlined on the form. The frequency and severity of 
common side effects of metformin will be rated on a 0 (none) to 3 (severe) scale. An open-ended side effects question will 
also be included. Furthermore, 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. 
 
Pill Count/Adherence. Medication adherence will be assessed by pill count at each study visit [65].  
 
3.3 Primary Outcomes 
 
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 “past week” time reference for all visits 
except the 24-h testing visit on Day 23, which will use a 24-h time reference. 
Neurocognitive Measures. Neuropsychological tests will be administered in a quiet laboratory testing room on a Dell® 
desktop computer running on the most recent and compatible version of Windows® at the CIRNA. Unless otherwise noted, 
all tasks will be administered via E-Prime 2.0 (Psychology Software Tools, Inc.). The computerized battery is administered 
in a random order using clickable icons.  Total administration time is ~ 45 min. The tasks are: 
 
• 
N-back Working Memory Task: In the traditional N-back task, sequences of letters or numbers are displayed and 
subjects respond with a button press to a single target using the following rules. The version of the N-back used in this 
study utilizes fractal images in place of letters or numbers. During the 1-back condition, subjects respond if the image 
is identical to the one preceding it.  In the 2-back condition, they respond if the stimulus is identical to the one two 
trials before.  In the 3-back condition they respond if the image is identical to the one three trials before.  The active 
baseline condition (0-back) is a simple target detection task. The primary outcomes will be total correct and correct 
reaction time (task duration: ~18 minutes). 
• 
Stop Signal Task (SST): The SST is a measure of response inhibition, or the ability to inhibit a prepotent response, and 
has been used in previous work with smokers [13]. In this task, participants are instructed to press labeled keyboard 
keys as quickly and as accurately as possible to indicate the direction the arrow faced (“z” for left; “/” for right). 
Following a 32-trial practice, stop signals (an 800-Hz, 100-ms, 70-dB tone) are presented on 25% of trials for a 32-trial 
practice and three task blocks of 64 trials each. The initial stop delay in each block is 250 ms and adjusts by 50 ms 
increments depending on whether the participant is able to successfully inhibit a response [67]. The adjusting stop 
delay allows the determination of the delay at which inhibition occurs on approximately 50% of trials. All trials consist 
of a 500-ms warning stimulus followed by a 1,000-ms go signal (left- and right-facing arrows) and 1,000-ms blank 
screen intertrial interval. Mean RT for each block is calculated based on valid responses (i.e., RT greater than 200 ms), 


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and only blocks with 20–80% inhibition and at least 80% accuracy are included in analyses. Stop signal reaction time 
(SSRT) is the primary dependent variable and is calculated by subtracting the mean stop delay from the mean RT on 
go-trials (task duration: ~10 minutes). 
• 
Color Shape Task: The Color Shape Task is a measure of flexibility. In each trial of this task (Miyake, Emerson, Padilla, 
& Ahn, 2004), a cue letter (C or S) appears above a colored rectangle with a shape in it (outline of a circle or triangle). 
Participants are instructed to indicate whether the color is red or green when the cue is C, and whether the shape was 
a circle or triangle when the cue is S. The colored rectangles are approximately 1.7” wide and 1.4” high, the circles 
were approximately 1.1” in diameter, and the triangles were 1.25” on each side. The color-shape figure appears in the 
center of the screen and the cue letters are centered 3/8” above its top edge. 
• 
HVLT Task: The Hopkins Verbal Learning Test – Revised (HVLT-R) assesses verbal learning and memory (immediate 
recall, delayed recall, delayed recognition) (Brandt, 1991). The task has been validated in individuals 16 to 92 years 
old and within brain-disordered populations (e.g., Alzheimer’s disease, amnestic disorders) as a measure of verbal 
learning and memory (Benedict et al., 1998). There are six alternate forms, each consisting of a list of 12 nouns 
(targets) with four words drawn from each of three semantic categories. The semantic categories differ across the six 
forms, but the forms are very similar in their psychometric properties. The HVLT-R has high test-retest reliability, and 
its construct, concurrent, and discriminant validity have been well-established (Shapiro et al., 1999). Raw scores are 
derived for Total Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index. Verbal 
memory has been shown to be a cognitive domain negatively affected by HIV infection (Antinori et al., 2007; 
Robertson and Yosief, 2014; Woods et al., 2004). There are two primary outcomes: Total Recall and Delayed Recall. 
Task duration is 5-10 min with a 25-min delay. 
• 
Delay Discounting Task: In this paradigm, participants choose between a smaller reward available immediately (e.g., 
$500 today) and a larger reward available after a longer delay (e.g., $1000 in a month). In this task, people differ in 
their degree of delay discounting, the extent to which they forgo larger monetary magnitudes in the future in order 
to obtain immediate rewards. As in previous work, the delayed reward will be fixed (e.g., $1000) and the magnitude 
of the immediate reward adjusts based on the subject’s responses (Du et al., 2002). Subjects will make 42 choices (6 
trials for each of 7 delays: 1 day, 1 week, 1 month, 3 months, 1 year, 5 years, and 25 years). The primary behavioral 
outcome will be the subject’s discount rate. Discount rates will be estimated by fitting a logistic regression that 
assumes a person’s decisions are a stochastic function of the difference in subjective value between the two options 
(Wileyto et al., 2004). Keeping with standard behavioral findings (Kable and Glimcher, 2007, 2010; Kirby and 
Santiesteban, 2003; Mazur, 1987), we will assume that subjective value (SV) is a hyperbolic function of the reward 
amount (A) and delay (D): SV = A/(1+kD), where k is the participant’s discount rate. Larger values of k indicate a greater 
degree of discounting future rewards. Participants will be told that the questions are hypothetical and that they should 
make their choices according to what they would choose if they were going to receive that amount. Task duration: 
approximately 5 minutes. 
 
3.4 Secondary 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 [68], as we have done previously [69] to assess self-reported smoking 
rate.  
 
Withdrawal Symptoms. The “Minnesota Nicotine Withdrawal Scale - Revised version”(MNWS_R) [70] captures the current 
state of nicotine withdrawal [71, 72]. 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 “past week” time reference for all visits except the 
24-H testing visit on Day 23, which will use a 24-h time reference.  
 
Craving. The 10-item brief QSU questionnaire on smoking urges [73] 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 [74]. This will be 
administered at all study visits (except the Intake). Similar to withdrawal symptoms, craving will be assessed using a “past 
week” time reference for all visits except the 24-H testing visit on Day 23, which will use a 24-h time reference. 
 


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Cigarette Ratings and Subjective Effects.  The Cigarette Evaluation Scale (CES), developed to assess subjective effects of 
smoking [75], is an 11-item Likert-format measure. Questions include items for nausea and dizziness, craving relief, and 
enjoyment of airway sensations. The Rose Sensory Questionnaire (SQ), a 9-item Likert-format measure, will be used to 
assess how much they liked the cigarette smoked and how high in nicotine the cigarettes appeared to be.  The 
questionnaire also includes a diagram of the respiratory tract and asks participants to rate the strength of the cigarette 
puffs on their tongue, nose, back of mouth and throat, windpipe, and chest. The CES and SQ will be administered at each 
visit following the Intake. 
 
 
 
Table 1. Study Measures 
State 
Intake 
Baseline Remote Check-In b 
Pre-Quit 
Testing 
24-H Abstinent  
Programmed Lapse 
Study Visit Days 
-1 
0 
7, 14 
21 
23 Part 1 
23 Part 2 
Screening Variables/Covariates 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Nicotine Dependence (FTND/Cigarette Brand) 
X 
 
 
 
 
 
Smoking/ETOH History 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Height/Weight* 
X 
X 
 
X 
 
 
Psychiatric/Substance Use Hx (MINI) 
X 
 
 
 
 
 
Suicidal Ideation/Bx (C-SSRS) 
X 
 
 
 
 
 
Bipolar Disorder Symptoms (MADRS, YMRS, additional 
screener)a 
X 
X 
X 
X 
X 
 
Carbon Monoxide (CO) 
X 
X 
 
X 
X 
X 
Blood Pressure 
X 
X 
 
X 
X 
 
Shipley Institute of Living Scale 
X 
 
 
 
 
 
Urine Drug Screen  
X 
X 
 
X  
X 
 
Pregnancy Screen 
X 
X 
 
X 
X 
 
Depression/Anxiety (HADS) 
X 
X 
X 
X 
X 
 
Functional Impairment (PAOFI) 
X 
 
 
 
 
 
Risk Assessment Battery (HIV+ group only) 
X 
 
 
 
 
 
BASIS-24 
X 
 
 
 
 
 
SF-12 
X 
 
 
 
 
 
Quick Inventory of Depression Symptoms 
X 
 
 
 
 
 
Liver and Renal Function test 
X 
 
 
 
 
 
Neuroinflammation (HIV+ group only) 
 
X 
 
X 
 
 
Blood Glucose 
 
X 
 
X 
X 
 
Treatment Variables 
 
 
 
 
 
 
Concomitant Medication Review 
 
X 
X 
X 
X 
 
Medication Side Effects 
 
X 
X 
X 
X 
 
Pill Count 
 
 
X 
X 
X 
 
Primary Outcomes  
 
 
 
 
 
 
Mood (PANAS) 
 
X 
X 
X   
X (24h) 
X (now) 
Neurocognitive Test Battery 
 
X 
 
X  
X 
 
Secondary Outcomes  
 
 
 
 
 
 
Cigarette Consumption (TLFB) 
 
X 
X 
X 
X 
X 
Withdrawal (MNWS-R) 
 
X  
X 
X   
X (24h) 
X (now) 
Craving (QSU-B) 
 
X  
X 
X   
X (24h) 
X (now) 
Subjective Effects, Cigarette Ratings (CES, SQ) 
 
X 
X 
X 
 
X 
 
*Note: Height and weight will be collected at intake visit, weight only will be collected at each subsequent study visit except day 23 
a Only administered if a diagnosis of bipolar disorder is self-reported or revealed via the MINI at intake 
b These visits will be completed remotely via phone or videoconference 


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2.  Statistical Analysis 
Sample size and analysis. For this analysis we will be estimating summary statistics by group, including means, standard 
deviations, within-subject correlations, and related confidence intervals.  Our sample of 18 per group will yield 95% 
confidence intervals with limits that fall less than 1/2 SD from the mean. For correlation, the 95% CI length will be no larger 
than 0.94 if r=0, and substantially narrower for r not= 0.  Because the goal of this study is to demonstrate feasibility and 
provide preliminary data, we will not conduct formal hypothesis testing. We will use these measures to estimate 
interaction effect sizes to plan future research. 
 
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.  
 
Data collected in MS Access and REDCap databases will be stored on a secure server administered by the Penn Medicine 
Academic Computing Services (PMACS) organization and will be restricted to only those individuals who are authorized to 
work on the trial. Individual user accounts with passwords will be used to restrict access to the database. Specific privilege 
assignments will also be employed so a user has access only to the functions necessary to complete applicable operations 
appropriate for their role in the trial. Additional measures to prevent unauthorized external access to the database 
environment will be employed using network firewall technologies. The Data Manager will maintain the database in an 
appropriate manner for the retention period required by regulation. Database administration includes user account 
maintenance, database security, performance monitoring, and database change management. Daily backups are 
performed to protect data against accidental destruction or corruption. 
 
Remote study sessions will be conducted via phone or via BlueJeans, which is a HIPAA-compliant platform with security 
features including a room lock to ensure that communications within the platform remain private. 
 
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 
• 
Medical Record Number 


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• 
Street address, city, county, zip code 
• 
Telephone numbers 
• 
Email address 
• 
Date of birth 
• 
Medical and drug use history 
• 
Social Security Number 
• 
Results from all questionnaires, tests, or procedures 
• 
Results from urine drug screening/pregnancy test 
• 
Results from blood for liver/kidney function test and glucose monitoring 
• 
Information on smoking, cognition, or HIV-related biomarkers from blood sample 
 
Potential participants will be contacted over the phone after responding to recruitment advertisements. Participants will 
undergo an initial phone screening where preliminary eligibility for the research study will be determined. Only if a 
participant is initially eligible, will they complete Intake tasks to confirm eligibility. All data collected over the phone and 
during in-person visits will be collected by research staff who have completed the CITI Protection of Human Subjects 
Research Training as well as HIPAA Compliance Training. Information will never be recorded with identifiers other than 
study ID. A separate list of names with ID numbers will be accessible only by authorized personnel. 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. Data will be accessible to the Study Investigators, Study Physician, 
study staff, UPenn IRB, Office of Clinical Research, authorized UPenn staff (e.g. accounting and billing matters, provide 
treatment, etc.) and the Food and Drug Administration. 
 
6.  Tissue Specimens 
Urine. A urine sample will be required at Intake and all testing sessions (Baseline, day 21 and day 23) for the drug and 
pregnancy screening. Participants who test positive for study prohibited drugs use may be deemed ineligible. Participants 
believed to have a false-positive result may continue in the study, with investigator approval. All female participants of 
child-bearing potential will complete urine pregnancy tests.  
 
Blood. One 8.5 mL sample of blood will be drawn at the Intake visit to evaluate liver and renal function. At the Baseline 
and Pre-Quit Testing visits four samples (two 10 ml and two 8.5 ml) will be drawn to assess neuroinflammatory markers. 
A drop of blood (approximately 0.3 microliter) will also be collected at each visit following the Intake to assess blood 
glucose levels. 
 
RISK/BENEFIT ASSESSMENT 
1.  Potential Study Risks 
Potential Risks of the Medication: The following are the common side effects that have been reported with metformin XR 
treatment:  diarrhea, nausea, and vomiting. Diarrhea led to discontinuation in 0.6% of patients. Side effects will be 
assessed at baseline and each subsequent visit (a total of 5 times throughout the study).  
  
In addition to the side effects mentioned above, other rare side effects of metformin XR have been reported including: 
lactic acidosis, abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, 
upper respiratory infection, and taste disturbance. 
 
All of these side effects shall be queried using a side effects checklist as described above. 
 
Metformin has been shown to be safe and well-tolerated in non-diabetic individuals including normal glucose tolerant, 
obese African Americans [76]; obese children and adolescents [77]; individuals at risk for developing diabetes [78]; and 
women with polycystic ovary syndrome [79]. Nevertheless, because metformin has the potential to lower blood glucose 
levels, even in non-diabetic individuals, participants’ blood glucose levels will be monitored at each study visit following 
the Intake (see Measures: Screening/Covariates for description).  
 
For individuals currently taking anti-retroviral (HAART) medications: There are no known HAART/metformin drug 
interactions. Specifically, metformin is not metabolized and is excreted unchanged in the urine. The non-nucleoside 
reverse transcriptase inhibitors, protease inhibitors, raltegravir, and maraviroc are hepatically cleared and are therefore 
not contraindicated. Because dolutegravir (Tivicay) or drugs that contain dolutegravir (e.g., Triumeq) can double 
metformin levels, participants taking dolutegravir will be limited to no more than 1000 mg metformin per day. Therefore, 
individuals taking dolutegravir will be force randomized to either the placebo condition or the low dose condition.  
 


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Stringent exclusion criteria are in place to limit the chance of these side effects. Liver and kidney function will be assessed 
at Intake to ensure participant safety. 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. Participants 
will be instructed to take the study medication once daily with their evening meal. They will also be warned 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. Schnoll) 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.  
 
Pregnancy: There are no adequate and well-controlled studies in pregnant women with metformin. Metformin was not 
teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the 
maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, 
respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Thus, 
metformin should not be used during pregnancy. All female participants of child bearing potential will complete a 
pregnancy test at the Intake session. 
 
Blood Draw: 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. 
 
Inflammation Results: The blood samples collected to evaluate markers of inflammation will be stored in the PMHARC 
Core Lab biobank, which can be accessed only by authorized study personnel. Because this is experimental, and we do not 
yet understand the role of these markers in smoking behavior, participants will not receive the results or feedback from 
the inflammation assays. 
 
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).  
 
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.  
 
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. 


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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 
 Data and safety monitoring board 
 
4.1 Data and Safety Monitoring Committee 
Data and Safety Monitoring will be conducted by the 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 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 004. 
 
The 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. Schnoll)/Co-I and Study Physician will work together to confirm eligibility criteria. The Study 
Physician/Nurse Practitioner and PI (Dr. Schnoll)/Co-I will review charts for each subject and will document reviews by 
signing and dating the final eligibility checklist in each chart, 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.   
 
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 84 subjects complete all study requirements.  On average, 3-4 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 004 and any 


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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. 
 
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. 
 
 


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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.  
 
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 and 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  
• 
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 an investigator. 
 
Adverse Event Attribution Categories:  
• Unrelated - The AE is clearly NOT related to the intervention  


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• Possibly - The AE may be related to the intervention  
• Probably - The AE is likely related to the intervention  
• Definitely - 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 metformin. 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. Participants will also complete 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. Trained 
staff will review participant responses and collect additional information as needed from the participant.  
 
Research staff are trained to inquire (time of onset, nature of issue reported, possible relation to metformin 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 PI/Co-I 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 metformin and is qualified to manage possible side effects. 
 
Based on published reports using the 500 and 1500 mg doses of metformin 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/investigator 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/investigator 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 and the ACC CTSRMC 
Notifying the Penn Institutional Review Board (IRB) 
A reportable event is an adverse event or incident that has the potential to be classified by the IRB as an unanticipated 


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problem posing risks to participants or others. In general, an incident is determined to be a reportable event when it is 
both 
1. unexpected in terms of nature or severity or frequency 
2. probably or definitely related to participation in the research. 
 
If an adverse event that meets these criteria, the IRB requires investigators to submit within 10 business days of discovery. 
However, if the event involved a death and indicates that participants or others are at risk of increased harm, investigators 
should report within 3 days. If the investigator does not have enough information to complete the Reportable Event form 
within this timeframe, a Reportable Event Form will be submitted and indicate that a follow up report will be provided 
once additional information has been obtained.  
 
Reportable Events include: 
 
(1) ADVERSE MEDICAL EVENTS WHICH ARE BOTH RELATED AND UNEXPECTED: 
• 
An event is considered “related to the research procedures” if the cause of the event is deemed probably or 
definitely related to the investigational product or a procedure that was performed for the purposes of the 
research. 
• 
A “suspected adverse reaction” could be considered a reportable event when there is reasonable possibility that 
the drug/investigational product caused the adverse event. For these reporting purposes, reasonable possibility 
means there is evidence to suggest a causal relationship between the drug/investigational product and the event 
• 
If the Sponsor determination notes a causal relationship between the event and the investigational drug/product 
without required revisions to the consent form or other study documents and/or the report indicates that the 
event does not alter the risk profile of the investigational drug/product, the event should not be classified as 
reportable 
• 
An event is “unexpected” if it is not accurately reflected in the protocol-related documents, such as the IRB-
approved research protocol, the investigator’s brochure/package insert, or, the current IRB –approved informed 
consent document. An event can also be considered unexpected if is not listed at the specificity or severity that 
has previously been observed and described in the protocol-related documents. 
• 
“Unexpected” also refers to events that are mentioned in the investigator’s brochure/package insert as occurring 
with a class of drugs or as anticipated, but, are not mentioned as to have been 
 
(2) UNANTICIPATED ADVERSE MEDICAL DEVICE REACTION: 
• 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated 
with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. 
 
(3) NON-MEDICAL EVENTS - THE IRB ALSO REQUIRES PROMPT REPORTING OF THE FOLLOWING EVENTS: 
• 
Withdrawal from marketing for safety concerns of a drug, device, or biologic used in a research protocol. 
• 
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by 
the research team 
• 
Breach of confidentiality 
• 
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 on the study 
• 
Premature completion of a study for any reason 
 
All adverse events that are not considered reportable events as defined above will be submitted to the IRB at the time of 
Continuing Review. 
 
Notifying the Abramson Cancer Center Clinical Trials Scientific Review and Monitoring Committee (ACC CTSRMC) 


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All adverse events meeting the following reporting requirements will be entered into the Penn Clinical Trials Management 
System (PennCTMS) AE/SAE form. 
 
On-Site subjects 
1. All grade 3 or higher events regardless of attribution or expectedness within 10 business days of knowledge. 
2. All unexpected deaths within two business day of knowledge. 
3. All others deaths within 30 days of knowledge. Deaths of subjects greater than 90 days from the last study 
treatment/intervention are not reportable unless a longer time frame is specified in the protocol. 
Exceptions: 
1. Grade 3 or 4 events that are judged by a Study Investigator to be clearly unrelated to protocol therapy. The reason 
for determining that the event is unrelated must be clearly documented in the source document. 
2. Grade 3 or 4 events that are probably or definitely related to progression of disease as judged by a Study 
Investigator. The fact that this event is related to disease progression must be clearly documented in the source 
document. 
3. Grade 3 or 4 events that are probably or definitely related to an FDA approved agent. The fact that this event is 
related to the FDA approved agent must be clearly documented in the source document. 
 
Protocol Exceptions 
An exception is 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 and 
ACC approval is required.  
 
Protocol Deviations 
A deviation is a one time, unintentional action or process that departs from the IRB and CTSRMC 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 major 
deviation must be reported to the ACC and the IRB within 10 business days of discovery.  
 
Minor deviations that do not meet the definition above will be explained in a memo to file or recorded on a deviation log 
and will contain documentation of an investigator’s assessment of the impact of the deviation on safety and study 
outcomes. Minor deviations will be reported to the IRB and ACC at the time of Continuing Review. 
 
Data, Safety and Monitoring Report.  An investigator 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 metformin. Research staff will monitor subjects closely during their 
participation. Data from this project will serve as preliminary data to formally test metformin as an adjunct medication to 
smoking cessation treatment.   


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SUBJECT COMPENSATION 
Participants will receive compensation for each session they complete and can receive up to $280 for completing all study 
requirements (including travel reimbursement). In place of $10/session to cover travel expenses, subjects may elect to 
use a round-trip car ride service (i.e., Lyft) which will be arranged and paid for in full by the research study. If they choose 
to use the ride service, they will not receive $10 for travel reimbursement and their total visit compensation will be up to 
$240. Travel will not be reimbursed for sessions designated as “in-person”, if they have to be completed by phone. 
 
Task completion compensation will depend on participants arriving on time for study visits and following study 
instructions. If they do not follow instructions, task completion compensation may be withheld.  
 
 The Greenphire ClinCard will be the primary form of payment for this study. The ClinCard is a reloadable, pre-paid card 
for the purposes of compensation. Compensation will be loaded onto the ClinCard within 24 hours of completed visits. 
Staff may ask participants to provide a Social Security Number, or complete a W-9 for this purpose, after determining eligibility 
so that a ClinCard can be assigned. Clincards may be mailed to subjects following the eligibility determination for the study.  
 
If a subject is found ineligible at any session due to any of the above-mentioned criteria, they will only be compensated 
$10 for travel, unless they have elected to use the ride service for that session.  
 
Subjects who successfully refer others to the program (i.e., person referred to program completes initial phone screen) 
will be awarded $20 per referral, for a maximum of 3 referrals. Compensation distribution is shown in the table below: 
 
Traveling via the Ride Service 
Participants may elect to use “Roundtrip”, which is a car ride service that partners with Lyft to coordinate roundtrip rides to 
study appointments. Participants will be asked for their preference when scheduling the Intake session via phone, and at 
each session preceding an in-person session once enrolled. Study staff will schedule each ride using participants’ first name, 
last name, and phone number via Roundtrip’s HIPAA compliant platform. Participants will receive a reminder call within 24-
48 hours prior to their study visit to confirm their visit, interest in using the ride service, and preferred pickup/drop-off 
locations. If the study staff cannot reach participants by 5pm the day prior to their study visit, their ride will be cancelled. 
Participants will still be permitted to attend the visit and will receive $10 to cover travel expenses. If participants need to 
cancel a previously confirmed ride, they must do so by contacting the study staff immediately, preferably by 5pm the day 
before their appointment. If participants fail to notify study staff within this timeframe, they may no longer be permitted to 
use the ride service at future study visits. Participants will be asked to provide a location within 15 miles of our center when 
booking the ride service.  
 
 
Day 
Study Visit 
Visit 
Compensation 
Task 
Completion 
Travel3 
Bonus 
Total 
-1 
Intake 
$20 
- 
$10 
 
$30 
0 
Baseline 
$30 
$10 
$10 
 
$50 
7 
Remote Check-In 
$10 
$10 
 
 
$20 
14 
Remote Check-In 
$10 
$10 
 
 
$20 
21 
Pre-Quit Testing 
$30 
$10 
$10 
 
$50 
23 
24-Hr Testing 
$40 
$10 
$10 
$501 
$110 
 
 
 
 
Study Total: 
$280 
N/A 
Referral Bonus 
 
 
 
$602 
$60 
 
 
 
 
Total w/ Referrals: 
$340 
1Bonus awarded for completion of ALL study visits 
2Table shows total compensation for three successful referrals 
3Only paid if subject opts-out of the round-trip car ride service; will not be paid if a visit has to be completed by phone 


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INFORMED CONSENT 
1. Consent Process 
Informed consent will be obtained using the combined consent and HIPAA form approved by the PENN IRB. This process 
will take place before study data are collected and prior to any treatment. The consenting process may occur remotely in-
person as part of the Intake session. If completed remotely, subjects will be contacted via Blue Jeans (HIPAA-compliant) 
for a videoconference or by phone. Reviewing the consent form will be completed using a RedCap survey and PowerPoint 
to visualize key points. Staff will email or text the survey link to subjects. The PowerPoint will either be sent to participants 
or shared using screen share via BlueJeans. Whether in person or remote, staff will review the study description, and all 
study procedures, potential risks, and information about the study medication will be addressed. Subjects will be given 
the opportunity to read the consent form in full. Following this, subject questions will be answered, and staff will 
administer comprehension questions to ensure subject understanding. Any incorrect answers will be addressed by the 
staff member completing consent. If remote, subjects will indicate within the RedCap survey if they wish to participate 
and will then be prompted to enter their First and Last name and sign the form using their finger or mouse. Subjects who 
are unable to provide an electronic signature may be mailed a physical version of the consent that must be mailed back 
to us prior to continuing with the Intake tasks. If needed, staff may also ask subjects to sign a physical version of the form 
at their first in-person visit for record keeping. Subjects will be able to download their signed version of the form from 
RedCap, and staff will also download a version to be saved to the electronic regulatory binder on our secure server, or, 
printed and placed in our physical binder. If in-person, subjects will receive a physical copy of the combined consent and 
HIPAA form for their records. Subjects will also be given the PI and Study Physician’s contact information should they wish 
to speak to either of them during the course of the study regarding their consent or the study procedures. The consent 
process will take place in English, there will be no waiting period, no coercion to participate, and all subjects will be 
considered competent to provide informed consent (i.e., they will be asked if they understand what they are consenting 
for). 
 
In collaboration with IRB Protocol #820043, HIV+ participants asked to provide additional blood samples at Baseline and 
PQ-Testing sessions will also be asked to complete the PMHARC Database and Specimen Repository consent form. This 
consent allows participants to grant permission for the storage of their data and/or samples, as well as allow future contact 
regarding new studies.  
 
2.  Waiver of Authorization 
Verbal consent will be attained from participants via phone for contact that occurs after their study participation has 
ended. This contact will only be made to collect data that they have already consented to provide as part of the study, 
and no additional PHI will be collected. Participants will have the option to not answer additional questions related to 
their participation in the study. If we are unable to get into contact with a participant, the data will be marked as missing. 
 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 
1. Staff Training 
Drs. Ashare and Schnoll 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. Systems for training and 
QA are established to ensure accurate eligibility screening and recruitment, accurate data collection, entry, and 
management, and optimal delivery of the study protocol. A new Manual of Operations (MOP) will be devised for this 
study, given unique procedures and measures. Dr. Metzger, who coordinates behavioral research within the PENN CFAR, 
will assist with staff training to ensure that unique issues related to the population are integrated into the MOP. Training 
sessions will occur over the first 3 months and annually. Monthly team meetings will review progress, assess adherence, 
and determine the need for protocol changes or additional training/QA. A study-specific Data and Safety Monitoring 
Committee will provide oversight. The MOP will ensure that the trial is conducted in a uniform manner over time and 
across staff. The MOP will describe roles and responsibilities for personnel and provide a detailed description of 
procedures for each point of contact with participants. For each visit/week, a checklist of events (e.g., measures, 


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counseling) will be created that will be completed by study personnel. CRFs will be created for each measure at each week, 
and every participant will have a study binder, with sections for every visit/week. Every visit will be milestoned (e.g., 
attended, missed, scheduled) to ensure proper tracking of participants. 
 
2. 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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