Clinical trial NCT02188459
Conditions: Smoking Nicotine Dependence
Sponsor: Henry Kranzler
Start date: 2014-10-30; Completion date: 2020-01-22
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Smoking during pregnancy adversely affects the health of the mother and her developing baby. Maternal smoking approximately doubles the risk of miscarriage, placental complications, preterm delivery, low birth weight and fetal and newborn death. The most common adverse effect of smoking during pregnancy is low birth weight, which sharply increases the risk of the newborn becoming ill or dying. In the US, maternal smoking is responsible for 30% of low birth weight babies, 10% of premature deliveries, and 5% of infant deaths. Fortunately, smoking cessation by pregnancy week 16, or as late as the third trimester, results in a near-normal weight infant at birth. Even reductions in smoking increase birth weight.

Despite the known risks, the majority of women who are smoking at the time of their first prenatal visit continue to smoke. Bupropion is approved by the US Food and Drug Administration (FDA) for smoking cessation in people who are not pregnant, but there are no carefully controlled studies on the use of Bupropion to help pregnant women quit smoking. Bupropion is also FDA approved to treat depression, and some pregnant women have taken it for that purpose, even though it has not been formally tested. The investigators propose to conduct a randomized, parallel-group, double-blinded, placebo-controlled, 10 week trial of Bupropion in 360 pregnant women who smoke daily and wish to quit smoking.

The study has three primary hypotheses. First, the investigators hypothesize that Bupropion treated subjects will decrease the frequency of smoking more than placebo-treated subjects. Second the investigators hypothesize that Bupropion treated subjects will have greater positive pregnancy and child health outcomes than placebo-treated subjects. Third the investigators hypothesize that Bupropion treated subjects will have decreased frequency of depressive symptoms and cigarette craving than placebo-treated subjects. These finding will provide information on the safety and efficacy of bupropion treat for smoking cessation in pregnant women.

Detailed description:
A. General Design: This is a phase II, prospective, placebo-controlled randomized controlled trial of the efficacy and safety of bupropion in combination with behavioral counseling for smoking cessation during pregnancy. Pregnant smokers (N=360) will receive bupropion or placebo treatment for 10 weeks, under strict double-blind conditions, with 3 post-treatment follow-up sessions: 2 and 6 weeks postpartum (with counseling to prevent relapse or encourage a repeat quit attempt) and monitoring of the persistence of treatment effects at 24 weeks post-quit date.

B. Recruitment: We will distribute IRB (Institutional Review Board)-approved brochures and posters to recruit pregnant women who smoke and wish to quit smoking through participation in the trial. At Penn Medicine sites, we will access the hospitals' EPIC computer programs to identify pregnant smokers receiving prenatal care and, working with their obstetrician, invite them to consider study participation. We will conduct a brief screening interview over the phone or in-person at the participant's obstetrics clinic to assess study eligibility criteria. Prospective participants who appear to meet eligibility criteria for the study will be scheduled for an in-person Informed Consent and Screening visit.

C. Screening Visit: Participants will read and sign the informed consent form, after all of their questions have been answered. Participants will then be asked to provide the researchers with information to determine whether they are eligible to participate in the study. On this visit, participants will be interviewed for about an hour. This interview will include questions about medical and pregnancy history, and any mood or other symptoms and determine the baby's date of delivery. We will also ask about any past or current use of alcohol, drugs, and cigarettes.

D: Baseline Visit: This in-person visit will be completed within 30 days of the screening visit and will last approximately 90 minutes. At the visit, we will measure heart rate and complete questionnaires by telephone and in person. We will take a blood sample (3 tubes, enough to fill 1.5 tablespoons) to be used to conduct genetic testing and to measure the body's ability to break down nicotine, which is contained in cigarettes.

At this visit participants will receive the first of six counseling sessions in the study. This first, "pre-quit" counseling session will last 30 minutes and will help to prepare them to quit smoking. They will be given study medication at this visit and will be instructed to begin taking it the following morning. They will be asked to identify a quit date within a week of beginning the study medication. They will start the study medication by taking one capsule (150 mg/day or placebo, a harmless, inactive substance) each morning for the first 3 days and then one capsule each morning and each evening (150 mg twice daily) for the remainder of the 10-week study treatment period. At this visit, and at every visit while taking the study medication, we will record any side effects that may have been experienced from the study medication. We will also ask participants to return all study medication that they have not taken and the study medication bottle.

The day after the Baseline Visit, the participants will begin to receive two daily text messages. The first message of the day (in the morning) will provide information on the expected development based on the baby's age, accompanied by a reminder to take the study medication. The second message of the day (in the evening) will ask the participants whether they took all of their study medication that day. They'll be asked to text back indicating that they received the message (in the morning) and whether they took the medication that day (in the evening). We will ask them which times they would like to receive the text messages each day. Although the information that they provide will help us to keep track of their participation, the inbox for our texting center is not monitored, so we will direct them to call our study staff to speak with them directly, rather than texting them if they have any study-related questions.

Visit C: Quit Date Visit: The scheduled quit date visit will occur approximately one week after the baseline visit and will last approximately 45 minutes. During this visit, we will measure the participants' heart rate and ask them to blow into an instrument that measures a chemical (carbon monoxide) that is in tobacco smoke. The study nurse will collect any medication not taken and the study medication bottle. The participants will receive a four-week supply of study medication and a study nurse will ask them about any study medication side effects that they may have experienced since starting the study. They will also be asked to complete some questionnaires and will receive 20 minutes of "quit-day" counseling, which will help them to identify things that could cause them to return to smoking and to develop a plan to avoid tempting situations.

Visit D: Week 3: This visit will occur by telephone and will last approximately 25 minutes, during which time the participants will be asked to complete questionnaires over the telephone. They will be asked about their cigarette use since the last visit and any medication side effects they may have experienced. They will also receive 10 minutes of counseling by phone to help them avoid smoking or, if they need to, set another quit date to try again to quit smoking.

Visit E: Week 5: This in-person visit will last approximately 30 minutes. The participants will be asked to complete some questionnaires and be interviewed about their cigarette use since the last visit. We will measure their heart rate and they will be asked to blow into an instrument that measures a chemical (carbon monoxide) that is in tobacco smoke. They will be asked to provide a blood sample (2 tubes, enough to fill 1 tablespoon) to be used to measure the concentration of study medication in the blood. The study nurse will collect any medication that the participants have left as well as the study medication bottle. They will receive a five-week supply of study medication and a study nurse will ask them about any study medication side effects that they may have experienced since starting the study. They will also receive 10 minutes of counseling to help they avoid smoking or, if needed, set another quit date to try quitting again.

Visit F: Week 7: This telephone visit will last approximately 15 minutes. The participants will be asked to complete some questionnaires. They will also be asked about their cigarette use since the last visit and any medication side effects they may have experienced.

Visit G: Endpoint visit: This in-person visit will last approximately 25 minutes. The participants will be asked to complete questionnaires and about their cigarette use since the last visit. During the visit we will measure their heart rate and they will be asked to blow into an instrument that measures a chemical (carbon monoxide) that is in tobacco smoke. The study nurse will collect any medication that they had not taken and the study medication bottle. The study nurse will ask them about any study medication side effects that they may have experienced since starting the study.

Visit H: Week 24 after the Quit Date: About six months after the participants started treatment, they will be contacted by telephone. During this phone call, a research technician will complete several questionnaires with them, similar to those they completed previously. Some participants will be asked to come back to the center following this interview to provide carbon monoxide breath samples as they did previously. Approximately two weeks prior to the phone call we may send a reminder letter that the phone visit is coming up.

Visits I and J: 2 and 6 weeks after delivery: The last two sessions will be held by telephone after the birth of the baby. The participants will be asked to complete several questionnaires, similar to those completed previously. They will also receive 10 minutes of counseling over the phone.

Arms: arm 1: Bupropion 150 mg BID, PO for 10 weeks arm 2: Placebo BID, PO for 10 weeks. The formulation appears identical to the bupropion capsules.
Interventions: intervention 1: Bupropion
Intervention descriptions: intervention 1: A total of 360 participants will be randomly assigned to one of two treatment conditions: Bupropion 300 mg/day (n = 180) or placebo (n = 180). We will use small-block randomization by site (Penn). A PHQ-9 score of 10 or greater will be used to identify major depression and stratify the randomization on it. Study site (Penn) will be the second of the two stratification variables.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
   HUMAN RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
 
Placebo-controlled trial of bupropion for smoking cessation 
in pregnant women 
 
 
 
Regulatory Sponsor: 
Henry R. Kranzler, M.D. 
Professor of Psychiatry 
University of Pennsylvania 
Perelman School of Medicine 
3535 Market Street Suite 500 
Philadelphia, PA 19104 
T: 215-746-1943 
C: 860-573-2184 
email: kranzler@mail.med.upenn.edu 
 
Funding Sponsor: 
National Cancer Institute 
Contact Person: Linda L. Mangino 
Manager of Administration & Finance 
CSA/Psychiatry 
University of Pennsylvania 
3440 Market Street, Ste. 370 
Philadelphia, PA  19104 
(484) 802-4375 
 
Study Product: 
Bupropion 
Protocol Number: 
820364 
IND Number: 
123026 
Protocol Version: 
Version  24 6/5/2019  
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
STUDY SUMMARY .................................................................................................................. 1-2 
1 
INTRODUCTION................................................................................................................. 3 
1.1 
BACKGROUND ............................................................................................................................. 3-7 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 7 
1.3 
PRECLINICAL DATA ..................................................................................................................... 7-8 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 8 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ....................................................................................... 8-10 
2 
STUDY OBJECTIVES ....................................................................................................... 10 
3 
STUDY DESIGN ................................................................................................................. 11 
3.1 
GENERAL DESIGN ........................................................................................................................ 11 
3.2 
PRIMARY STUDY ENDPOINTS ................................................................................................... 11-12 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................... 12 
3.4 
SAFETY ENDPOINTS ..................................................................................................................... 12 
4 
PARTICIPANT SELECTION AND WITHDRAWAL .................................................. 12 
4.1 
INCLUSION CRITERIA .................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA .............................................................................................................. 12-13 
4.3        PARTICIPANT RECRUITMENT AND SCREENING ................................................................................. 13 
4.4 
EARLY WITHDRAWAL OF PARTICIPANTS ......................................................................................... 13 
 
4.4.1      WHEN AND HOW TO WITHDRAW PARTICIPANTS ................................................................ 13 
 
4.4.2     DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS ................................. 13 
5 
STUDY DRUG .................................................................................................................... 13 
5.1 
DESCRIPTION ............................................................................................................................... 13 
5.2 
TREATMENT REGIMEN .................................................................................................................. 14 
5.3 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ............................................ 14-15 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 15 
5.5 
PARTICIPANT COMPLIANCE AND MONITORING ................................................................................ 15 
5.6 
PACKAGING ................................................................................................................................. 15 
5.7 
BLINDING OF STUDY DRUG ........................................................................................................... 15 
6 
STUDY PROCEDURES .................................................................................................... 16 
6.1 
RECRUITMENT ........................................................................................................................ 16-17 
6.2 
VISIT A: INFORMED CONSENT & SCREENING  ................................................................................. 17 
6.3 
VISIT B: BASELINE PRE-QUIT ................................................................................................... 18-19 
6.4 
VISIT C: WEEK 1 TARGET QUIT DAY ............................................................................................. 19 
6.5 
VISIT D: WEEK 3  ......................................................................................................................... 19 
6.6 
VISIT E:  WEEK 5 .................................................................................................................... 19-20 
6.7 
VISIT  F: WEEK 7 .......................................................................................................................... 20 
6.8  
VISIT G:  WEEK 10 ENDPOINT ....................................................................................................... 20 
6.9  
VISIT H: WEEK 24 POST-TQD ...................................................................................................... 20 
6.10  
VISIT I & J: POSTPARTUM WEEK 2 AND WEEK 6 ............................................................................. 20 
6.11 
EARLY TERMINATION VISIT  .......................................................................................................... 20 
6.12  
OTHER STUDY PROCEDURES AND CONSIDERATIONS ................................................................ 20-21 
7 
STATISTICAL PLAN ........................................................................................................ 21 
7.1 
POWER ........................................................................................................................................ 21 
7.1.1 Aim 1 ................................................................................................................... 21-22 


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7.1.2 Aim 2 ........................................................................................................................ 22 
7.2 
STATISTICAL ANALYSES ........................................................................................................... 22-23 
7.2.1 Missing Data ............................................................................................................. 23 
7.2.2 Specific Aim 1 ..................................................................................................... 23-24 
7.2.3 Specific Aim 2 .......................................................................................................... 24 
7.2.4 Specific Aim 3 .......................................................................................................... 24 
7.3 
PARTICIPANT POPULATION FOR ANALYSIS ..................................................................................... 25 
8 
SAFETY AND ADVERSE EVENTS ................................................................................ 25 
8.1 
DEFINITIONS ........................................................................................................................... 25-26 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 26 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 27 
8.3.1 IRB Notification by Investigator .............................................................................. 27 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 27 
8.5 
MEDICAL MONITORING ................................................................................................................. 27 
8.6 
PROTECTION OF PARTICIPANTS ............................................................................................... 27-28 
9 
DATA HANDLING AND RECORD KEEPING ............................................................. 28 
9.1 
CONFIDENTIALITY .................................................................................................................... 28-30 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 30 
9.3 
CASE REPORT FORMS.................................................................................................................. 30 
9.4 
RECORDS RETENTION .................................................................................................................. 30 
10 STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 30 
10.1 
STUDY MONITORING PLAN ....................................................................................................... 30-39 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 40 
11 ETHICAL CONSIDERATIONS ....................................................................................... 40 
11.1 
CONSENT PROCEDURES ............................................................................................................... 40 
12 STUDY FINANCES............................................................................................................ 40 
12.1 
FUNDING SOURCE ........................................................................................................................ 40 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 40 
12.3 
PARTICIPANT STIPENDS OR PAYMENTS .................................................................................... 40-41 
13 REFERENCES ............................................................................................................... 41-51 
14    APPENDIX ………………………………………………………………………………..56 
14.1 
DATA AND SAFETY MONITORING PLAN ............................................................................................ 56 
14.2 
CLINCARD DATA SECURITY AND PRIVACY STATEMENT .................................................................. 62 
 
      
 
  


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Study Summary 
Title 
Placebo-controlled trial of bupropion for smoking cessation in pregnant women 
Short Title 
Bupropion Study 
Protocol Number 
820364 
Phase 
Phase II 
Methodology 
This is a prospective, placebo-controlled RCT of the efficacy and safety of 
bupropion in combination with behavioral counseling for smoking cessation 
during pregnancy.  Pregnant smokers (N=360) will receive bupropion or 
placebo treatment for 10 weeks, under strict double-blind conditions.  
Study Duration 
Approximately 54 months 
Study Center(s) 
Multicenter study: University of Pennsylvania (Penn): Dickens Women’s 
Health Center (DWHC) at the Hospital of the University of Pennsylvania 
(HUP) and Pennsylvania Hospital (PAH) Thomas Jefferson University: 
Jefferson University Department of Obstetrics and Gynecology Associates 
(JOGA) and Maternal Addiction, Treatment, Education and Research Center 
(MATER; Jefferson) and Christiana Care Hospital System, Newark, DE. 
Objectives 
Specific Aim 1:  Conduct a 10-week placebo-controlled trial of bupropion 
300 mg/day in 360 pregnant smokers who are at 13–26 weeks gestation. We 
will monitor smoking behavior and adverse effects (AEs) of the medication 
during a 10-week treatment period.  A post-treatment follow-up visit will be 
held at 24 weeks post target quit date (post-TQD).  We will also provide two 
booster counseling sessions at weeks 2 and 6 postpartum and a final 
research evaluation at 24 weeks post-TQD.  We will use text messages to 
send pregnancy-relevant information and medication-adherence cues to 
improve medication adherence. In addition to examining the effect of 
treatment on smoking cessation, we will monitor its effects on pregnancy 
outcomes (length of gestation, rate of pregnancy complications, and birth 
outcomes). 
 
Specific Aim 2:  Assess changes in depression symptoms and craving as 
mediators of bupropion’s effect on quit rates.  
 
Exploratory Aim:  Explore genetic, metabolic, and social/behavioral 
moderators of the efficacy of bupropion on cigarette abstinence and safety. 
To generate new hypotheses, we will explore whether the risk of AEs and the 
efficacy of bupropion treatment (vs. placebo) are moderated by: 1) the rate of 
nicotine metabolism (i.e., nicotine metabolite ratio (NMR)] and variation in 
CYP2A6; 2) variation in CYP2B6 and plasma concentrations of bupropion 
and hydroxybupropion; and 3) variation in social/behavioral variables, 
including weight concerns, body image, and the presence of other smokers in 
the home. 
Number of Participants 
360 
Diagnosis and Main 
Inclusion Criteria 
Pregnant Smokers who are at 13-26 weeks gestation. 
Study Product, Dose, 
Route, Regimen 
Bupropion tablets and matching calcium carbonate tablets as placebo for 
blinding.  Maximum bupropion daily dosage is 300 mg by mouth per day.  
Dosing will be for 3 days at 150 mg per day and then 150 mg twice daily.  
Duration of 
administration 
10 weeks 


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Reference therapy 
placebo 
Statistical 
Methodology 
Preliminary analyses will assess sample characteristics (e.g., age, race, study 
site) by treatment using t-test or contingency table methods. These variables 
will also be examined for their relationship to completion of outcome 
assessments. Variables related to treatment arm or completion of follow ups 
will be included as covariates in analyses of study aims. Compliance 
measures will be evaluated across treatment arms, and controlled for in 
primary analyses. We will use intent-to-treat as the primary method to 
evaluate study aims.  For Aim 1, we will test treatment group differences in a 
binary abstinence outcome that is a repeated measure using a generalized 
estimating equations (GEE) model with a logit link.  Quit rates after 10 weeks 
of study medication and at 24 weeks post-TQD will represent our primary 
outcome variables.  Medication group (bupropion vs. placebo) and time point 
(10 and 24 weeks) will be treated as categorical predictor variables, and the 
model will predict separate effects of treatment on abstinence at each time 
point (an interaction).  Mean birth weight will be compared for treatment 
groups using a two-sample t-test, in the context of multiple linear regression. 
We will also compare treatment arms for equivalence of the frequency of 
moderate-to-severe adverse events (individual and total).  For Aim 2, we will 
use a regression-based path model approach to examine mediation of 
treatment effects by changes in depression and craving scores, which will be 
entered in the model as standardized pre-post differences, continuously 
distributed and treated as normal in linear regression. The effects of 
treatment arm on mediators, and of mediators on outcome, will be assessed 
using linear regression and standardized variables.  For Aim 3, we will 
explore whether the risk of adverse events and the efficacy of bupropion 
treatment (vs. placebo) is moderated by: 1) the rate of nicotine metabolism 
and variation in CYP2A6; 2) the rate of bupropion metabolism (i.e., variation 
in CYP2B6 and plasma concentrations of bupropion and hydroxybupropion); 
and 3) variation in social/behavioral variables, including weight concerns, 
body image, and the presence of other smokers in the home.   
 
 
 


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1. Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1. 
Background 
Smoking During Pregnancy is a Major US Public Health Problem: Smoking during 
pregnancy is a major modifiable cause of poor pregnancy and child health outcomes in the US 
(1, 2).  Maternal smoking increases the risk of a number of serious adverse outcomes of 
pregnancy, including spontaneous abortion, placental complications, preterm delivery, and fetal 
and neonatal death.  The most consistent adverse effect of smoking during pregnancy is low 
birth weight (LBW, i.e., <2500 g) (1, 24, 25), the risk of which doubles with maternal smoking 
(2).  In turn, LBW (particularly very low birth weight, i.e., <1500 g), exponentially increases 
morbidity and mortality risk (3).  In the US, maternal smoking is responsible for 30% of LBW 
babies, 10% of premature deliveries, and 5% of infant deaths (7).  Fortunately, smoking 
cessation by 16 weeks gestation (9, 10), or as late as the third trimester (10), results in a near-
normal birth weight infant.  Reductions in smoking also increase birth weight (26).  Despite 
these risks, the majority of women who are smoking at the time of their first prenatal visit 
continue to smoke, risk factors for which include being unmarried, less educated, heavier 
smokers (>1/2 pack per day), depressed, with partners who smoke (27-30).  
Interventions for Smoking Cessation in Pregnant Smokers: 
Behavioral Interventions for Smoking in Pregnancy:  Smoking cessation efforts in pregnant 
women have depended largely on behavioral interventions alone, despite consistent evidence 
that combining behavioral and pharmacologic strategies is more effective than either alone.  A 
meta-analysis of 72 trials (11), including randomized controlled trials (RCTs) in over 20,000 
pregnant smokers, showed a modest reduction in smoking by women who received a 
behavioral intervention relative to usual care [risk ratio (RR) = 0.94].  Babies born to women in 
the intervention groups were less likely to have a low birth weight (RR = 0.83) and to be born 
preterm (RR = 0.86).  Mean birth weight was 53.9 g (95% CI = 10.44 g to 95.40 g) greater in the 
intervention groups.  A review of the findings from six controlled trials with pregnant smokers of 
lower socioeconomic status (SES) showed that financial incentives for smoking cessation was 
efficacious during pregnancy and the early postpartum period, with abstinence rates several-fold 
those of controls (31).  The intervention also improved estimated fetal growth, mean birth 
weight, and the percentage of low-birth-weight infants.  The high cost of the incentives limits the 
impact of this approach, particularly in public settings with limited funding.  Further, there were 
high relapse rates once the incentives were removed.  
Behavioral interventions for smoking among pregnant women are limited by several other 
factors. First, they are least effective in heavier smokers, with a quit rate of 20% in pregnant 
women who smoke <10 cigarettes per day (CPD), 15% in women who smoke 10-19 CPD, and 
5% in women who smoke >20 CPD (32). Second, they are less effective at mitigating nicotine 
abstinence effects (e.g., craving/withdrawal) than pharmacotherapy (e.g., bupropion; ref. 33).  
Pregnant women report that nicotine withdrawal symptoms and craving are major reasons for 
their inability to quit smoking (34). Third, behavioral interventions are generally less efficacious 
than pharmacotherapy in treating ND in depressed smokers (33).  Upwards of 12% of pregnant 
women have depression (1) and upwards of 50% of depressed pregnant women smoke (8).  
African American pregnant smokers with elevated depression symptom scores were half as 
likely as women with lower depression scores (17) to consider seriously quitting smoking during 
pregnancy. Fourth, women with low annual incomes are half as likely as those with higher 


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incomes to quit smoking during pregnancy (35), with behavioral interventions of particularly low 
efficacy in lower SES women (36, 37).  Finally, women–especially pregnant women–are faster 
metabolizers of nicotine (13), making them less likely to respond to behavioral smoking 
cessation interventions and more likely to respond to pharmacotherapy (i.e., bupropion; ref. 15). 
The utility of a smoking cessation treatment in pregnant women depends on its efficacy in 
smokers with greater severity of ND, craving and withdrawal, a high rate of co-morbid 
depression, more rapid nicotine metabolism, and economic disadvantage, which characterize 
many pregnant smokers (38).   
Pharmacologic Interventions for Smoking.  Several medications are FDA approved for 
smoking cessation in non-pregnant smokers.  Nicotine replacement therapies (NRTs) partially 
replace the nicotine usually derived from smoking, relieving craving and other withdrawal 
symptoms (39, 40).  The odds ratio (OR) of abstinence with NRTs compared to placebo varies 
from 1.5 for the nicotine gum to 2.3 for the nasal spray (12).  Bupropion, a non-nicotine 
medication first approved by the FDA as an antidepressant, inhibits the neuronal reuptake of 
dopamine and norepinephrine (41).  It has an OR of 2.1 for smoking cessation (12) and has 
been shown to reduce depressive symptoms in smokers (42), particularly smokers with high 
baseline depression (52). Varenicline, an α4β2 nicotinic receptor partial agonist (44), has an OR 
of 3.1 in promoting smoking cessation (12).  However, there are no safety data on the use of 
varenicline for pregnant smokers.  As discussed below, bupropion may be especially efficacious 
for smoking cessation in pregnant women.  
Studies of NRT for Smoking Cessation during Pregnancy: In an effectiveness study 
(45), pregnant smokers received cognitive-behavioral therapy (CBT) and were randomly 
assigned to receive a choice of NRT (gum, patch, or lozenge) or no medication. Although the 
quit rate in the NRT group was approximately double that of the comparison group, the study 
was stopped because the NRT group had twice the serious adverse event (SAE) rate of the no-
medication group.  After adjusting for a history of preterm delivery, which was the most common 
SAE, the difference in SAE rate between groups was not statistically significant (p=0.09). Three 
efficacy studies of NRT have been conducted in pregnant smokers (46-48). In a Danish study 
(46), all women received counseling and either 6 weeks of a nicotine patch or placebo.  At the 
end of pregnancy, neither quit rates nor mean CPD differed by group.  However, patch 
compliance was poor (i.e., the average use being only 2 weeks).  In a US study (47), 194 
pregnant smokers were randomly assigned to receive treatment with 2 mg gum or placebo 
combined with individual behavioral counseling. Smoking cessation rates were non-significantly 
higher in the NRT group.  Importantly, despite limited adherence to NRT, it produced a greater 
reduction in CPD and cotinine concentrations than placebo and was associated with better 
treatment retention.  Mean (SD) birth weight [3287 g (SD=569) vs. 2950 g (SD=657); p<0.001] 
and mean gestational age [38.9 weeks (SD=1.7) vs. 38.0 weeks (SD=3.3); p=0.014] were 
significantly greater in the nicotine group.  In a UK study (48), 1,050 pregnant smokers were 
randomly assigned to nicotine patch or placebo for 8 weeks, combined with behavioral 
counseling.  Although the quit rate was higher at 1 month in the NRT group (21.3% vs. 11.7% 
for placebo), the rate of abstinence from the quit date until delivery did not differ significantly 
(9.4% for NRT and 7.6% for placebo).  Importantly, however, adherence was very low.  Thus, 
NRT does not enhance quit rates in pregnant women, possibly due to the higher rate of 
metabolism (i.e., inactivation) of nicotine in pregnancy and poor medication adherence in the 
studies. 
Rationale for the Choice of Bupropion for Smoking Cessation During Pregnancy: To 
date, there are no published studies of bupropion SR for smoking cessation during pregnancy 
(49).  There are several reasons to evaluate bupropion in the treatment of pregnant smokers. 
First, pregnancy increases the rate of nicotine metabolism (13), which diminishes 


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responsiveness to behavioral interventions and NRT (14, 15).  Bupropion, by contrast, is 
efficacious for smoking cessation in fast metabolizers of nicotine (15).  Second, although 
precise statistics are not yet available on the frequency with which bupropion is prescribed to 
pregnant women, it was the fourth most commonly prescribed antidepressant in pregnancy in 
2007 (16).  Moreover, bupropion in combination with cognitive behavioral therapy appears to 
promote greater smoking cessation rates and a longer time to relapse than placebo among 
women with smoking-related weight concerns (50), a potential contributing factor to smoking 
and relapse in postpartum smokers, including lower SES women (51).  Further, depressive 
symptoms are common in pregnant women and are linked to continued smoking and data 
suggest that depressed smokers may respond better to bupropion than non-depressed smokers 
(52). Finally, bupropion appears to be safer than NRT for use in pregnancy.  De Long et al. (53) 
examined the effect of fetal and neonatal exposure to bupropion on postnatal metabolic and 
reproductive outcomes in rats.  In contrast to fetal exposure to nicotine (54), exposure to 
bupropion did not adversely affect metabolic outcomes or the fertility of the female offspring. 
Lastly, a small, preliminary study (55) showed that bupropion reduced CPD and improved mood 
among pregnant smokers more than citalopram/escitalopram. 
In summary, behavioral interventions for smoking cessation in pregnant women are of 
limited efficacy, failing to adequately address several factors that are particularly relevant to 
smoking in this population (e.g., depression, rate of nicotine metabolism). Of the first-line 
medications, NRT has shown limited efficacy in pregnant smokers and in animal models of fetal 
exposure is associated with a number of potential adverse effects on offspring.  Although 
varenicline is efficacious in non-pregnant smokers, there is an absence of safety data on its use 
in pregnancy.  Bupropion is efficacious in non-pregnant smokers, is less likely to cause adverse 
fetal effects than nicotine, and is efficacious in fast metabolizers of nicotine and smokers with 
depressive symptoms and weight concerns (all factors that are common during pregnancy).  
Thus, we propose to conduct the first adequately powered RCT of bupropion to treat ND in 
women who continue to smoke during the second trimester of pregnancy.  
Mediators and Moderators of Bupropion Response  
Depressive Symptoms and Craving as Mediators of Bupropion’s Therapeutic Effects: 
Pregnant smokers who are depressed are less likely to quit smoking than those who are not 
(28).  In pregnant minority women, even mild depression nearly doubled the risk of continued 
smoking (56). Thus, we expect that, given bupropion’s well-established antidepressant effects 
(57, 58), its efficacy as a treatment for ND will be mediated by reductions in depressive 
symptoms.  Likewise, several symptoms that are present in pregnant smokers before quitting 
smoking (e.g., irritability, anxiety, difficulty concentrating, insomnia, restlessness, increased 
appetite, depressed mood, drowsiness) are similar to those that occur commonly during nicotine 
withdrawal (59).  Compounded by nicotine withdrawal, these symptoms may make it more 
difficult for pregnant women to quit smoking (34).  Because bupropion mitigates craving 
associated with nicotine abstinence, we expect that its efficacy in treating ND in pregnant 
women will also be mediated by a reduction in craving. 
Metabolic, Genetic, and Social/Behavioral Moderators of Bupropion’s Efficacy.   
i. The rate of nicotine metabolism [i.e., the nicotine metabolic ratio (NMR)] is largely 
heritable (60-63) and several functional polymorphisms in the CYP2A6 gene that affect enzyme 
activity have been characterized by Dr. Tyndale, a consultant to this project (64-65). However, 
as-yet-unidentified variants in CYP2A6 also account for heritability in nicotine clearance (63), 
the rate of which is also influenced by age, sex, hormonal factors, and smoking (65-66). A 
genetically informed biomarker, the NMR, is based on the measurement of two long-lasting 
nicotine metabolites and can overcome these genotype limitations. The NMR reflects CYP2A6 
activity and the influence of other genetic and environmental influence on nicotine clearance in 
vivo (66-68). The NMR can be assessed non-invasively (e.g., from saliva, urine, or plasma) 


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without additional drug administration, using metabolite levels from nicotine derived from the 
smokers’ usual cigarettes. Results are highly reproducible and independent of time since last 
cigarette (67).  Lastly, the NMR is strongly correlated with nicotine clearance (r=.70-.95), and 
CYP2A6 genotypes, in smokers of European (68-71) and African ancestry (64, 72). Importantly, 
NMR has been associated with smoking cessation and response to therapy in independent 
clinical trials (73). Smokers characterized as slow metabolizers of nicotine (the lowest quartile of 
the NMR) have significantly higher quit rates on NRT than faster metabolizers (higher three 
quartiles of the NMR) (70, 74); the same is true in African American smokers (72).  In an RCT of 
bupropion, slow metabolizers had high quit rates on placebo, which were not enhanced by 
bupropion.  In contrast, fast metabolizers showed high quit rates only with bupropion (15). Thus, 
we will examine NMR as a moderator of treatment response on the hypothesis that slow 
metabolizers will do well on either placebo/counseling alone or bupropion, while fast 
metabolizers will achieve little benefit from counseling alone (i.e., placebo), but will respond well 
to bupropion. This has implications for personalizing smoking cessation treatment in pregnant 
women. 
ii.  Variation in CYP2B6. Two studies from Dr. Tyndale’s group have also shown that a 
variant (CYP2B6*6) in the gene encoding the cytochrome P450 enzyme 2B6 (which 
metabolizes bupropion to its major active metabolite, hydroxybupropion) moderated bupropion 
response.  First, in a study of 326 Caucasian smokers (75), at the end of treatment and at 6-
month follow up, carriers of the variant allele (45% of the sample) had significantly higher quit 
rates than placebo-treated subjects (32.5% vs. 14.3 and 31.2% vs. 12.9%, respectively).  In the 
group with no variant alleles, bupropion treatment was no better than placebo in promoting 
abstinence.  Second, in a 7-week treatment trial in 540 African-American light smokers (<11 
CPD), 42.9% of bupropion-treated subjects were not adherent to treatment (20).  In the 154 
treatment-adherent bupropion subjects, higher hydroxybupropion (but not bupropion) 
concentrations resulted in higher rates of smoking cessation after 3, 7, and 26 weeks of 
treatment (ORs = 2.82, 2.96, and 2.37, respectively).  Using alleles that have been shown to 
encode a reduced-function enzyme, Tyndale and colleagues found that the slow metabolizer 
group had significantly lower hydroxybupropion concentrations and both the slow metabolizer 
and intermediate groups had lower hydroxybupropion/bupropion ratios than faster metabolizers.  
Because 16% of African Americans and 6% of Caucasians are slow metabolizers, with the 
proportion of intermediate metabolizers in these groups being 48% and 38%, respectively, the 
potential for variation in CYP2B6 to moderate treatment response is substantial.  However, 
because of other influences on bupropion and hydroxybupropion concentrations (e.g., 
concomitant medications, hormone status, and bupropion adherence), there are inconsistent 
findings on the impact of CYP2B6 variation on smoking cessation.  In the present study, we will 
measure CYP2B6 genotype, bupropion and hydroxybupropion concentrations, medication 
adherence, and enzymatic activity and the impact of these on the likelihood of smoking 
cessation (and risk of AEs). 
iii.  Smoking-related weight concerns and body image influence smoking initiation, cessation 
and relapse by female smokers (76) and may be of particular concern during pregnancy and the 
postpartum period, when women’s focus on weight gain and weight loss are heightened (51, 77, 
78). Pregnant women with greater weight concerns are more likely to continue smoking as a 
maladaptive weight control strategy, report greater appetite and weight gain as nicotine 
withdrawal symptoms, have lower confidence in quitting in the face of weight gain, and are less 
likely to quit smoking during pregnancy (77-79). Smoking-related weight concerns affect women 
across populations, including women in minority and low income communities, and may be 
related to broader patterns of body image preoccupation (50, 51, 79-81). Bupropion can offset 
the increased appetite associated with nicotine withdrawal (82).  It could also reduce the 
adverse influence of weight concerns on quit rates, making such concerns an important 
potential moderator of response to the medication.  


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iv. Effects of other smokers in the home.  General and cessation-specific social supports are 
important in promoting smoking cessation and preventing relapse in women smokers. Despite 
support, the presence of other smokers in the home can undermine efforts to change smoking 
behavior (83-86). Smoking mothers in a Healthy Start program that included a smoking 
cessation intervention were more likely to quit smoking and maintain abstinence if they did not 
have other smokers living at home (84). The negative influence of other smokers in the home on 
women’s abstinence during pregnancy has also been seen (83), warranting an examination of 
the potential moderating effects of such circumstances on smoking cessation with bupropion. 
Text Messaging to Enhance Adherence with Bupropion Treatment: Poor treatment 
adherence in smoking cessation RCTs is a key factor limiting treatment effects (87).  In 2012, 
2.27 trillion text messages were sent in the US 
(http://www.ctia.org/advocacy/research/index.cfm/aid/10323), providing a novel method to 
communicate health messages, including sending medical appointment reminders (88-90), 
providing medical test results (91), monitoring patients’ AEs (92), and enhancing medication 
adherence (22, 23, 88, 93, 94).  
Women often report that during pregnancy they seek pregnancy-related information on the 
Internet (95). Of particular interest to mothers are websites that present information on fetal 
development with content that is individually tailored to their due date or stage of pregnancy (95-
98).  Combining medication reminders with daily pregnancy-related topics may be particularly 
useful to enhance adherence because women: a) will identify with the information; b) find it 
engaging and personalized; and c) find that it serves both a reminder and an information 
function (99).  In a survey of pregnant women conducted at public hospitals and health centers, 
96% reported that they would like to receive text messages with information regarding prenatal 
care, health of the fetus, and other pregnancy educational information (100). Thus, we will utilize 
a personalized text-messaging system with high relevance for pregnant women to promote 
medication adherence. 
To allow all participants to receive text messages, we will offer them cell phones with 
unlimited domestic talk and text for up to 32 weeks of study participation. The phones will also 
allow study staff to more readily contact participants and to complete the phone counseling 
visits.  The phones will not have a data plan nor will they allow international calls or text.  
Participants will have the option to refuse the phone. Participants will not be responsible for the 
cost of lost or stolen phones. We will replace a lost or stolen phone once during the study. 
Significance: The aims proposed here may increase scientific knowledge and improve clinical 
practice in an area with enormous public health implications by improving the outcome of 
pregnancies in women who smoke while pregnant. This study will be the first adequately 
powered RCT to examine both the efficacy and safety of bupropion for ND treatment in this 
subgroup of smokers.  Moreover, the study will provide important information on mediators and 
moderators of bupropion’s efficacy and demonstrate the use of a novel text-messaging system 
to promote treatment adherence in this population. 
1.2. 
Investigational Agent 
Bupropion is an aminoketone antidepressant with an additional indication for smoking cessation.  
It is chemically unrelated to other known antidepressants including tricyclics, tetracyclics, or 
selective serotonin re-uptake inhibitors. Bupropion weakly inhibits the neuronal uptake of 
norepinephrine and dopamine, but does not inhibit monoamine oxidase or serotonin reuptake. 
Pharmacologic activity is postulated to be mediated by noradrenergic and/or dopaminergic 
mechanisms. The mean elimination half-life is approximately 21 hours, and steady-state is 
reached within 8 days. These and other pharmacokinetic parameters in cigarette smokers did 
not differ from those in non-smokers. For smoking cessation, the usual dose of bupropion is 150 
mg twice daily, please see attached Investigator’s Brochure with medication Package Insert). 


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1.3     Preclinical Data 
In animal studies, bupropion had pharmacologic activity similar to psychostimulants, eliciting 
mild stereotyped behaviors and an increased rate of response to several schedule-controlled 
behavior paradigms in rodents. In positive reinforcement studies, primates self-administered 
bupropion.  In response to bupropion, rats displayed amphetamine- and cocaine-like 
discriminative stimulus effects. 
Bupropion administered orally to rats and rabbits at doses up to 450 and 150 mg/kg/day, 
respectively, showed no clear evidence of teratogenic activity. A slightly increased incidence of 
fetal malformations and skeletal variations were observed in rabbits. Decreased fetal weights 
were seen at doses of 50 mg/kg and greater.  In another study, rats administered bupropion at 
oral doses of up to 300 mg/kg/day throughout pregnancy and lactation produced offspring 
showing no apparent adverse developmental effects (Zyban Package Insert). 
1.4.   Clinical Data to Date 
No placebo-controlled trial of bupropion has been conducted in pregnant women to treat either 
depression or promote smoking cessation.  Bupropion is classified as FDA Pregnancy Category 
C, meaning that although animal studies have shown an adverse effect on the fetus, there are 
no well-controlled studies in humans and the potential benefits of use during pregnancy may 
outweigh the risks. 
One retrospective study examined 7,005 antidepressant-exposed pregnancies in a managed-
care database. The study showed no greater risk for congenital malformations among the 1,213 
bupropion-exposed first-trimester pregnancies than for other first-trimester antidepressant 
exposures or to bupropion use during the second or third trimesters (Zyban Package Insert). 
Bupropion was the fourth most commonly prescribed antidepressant in pregnancy in 2007 (16). 
1.5  Dose Rationale and Risk/Benefits 
To date, there are no published placebo-controlled studies of bupropion SR for smoking 
cessation during pregnancy (49).  There are several reasons to evaluate bupropion in the 
treatment of pregnant smokers. First, pregnancy increases the rate of nicotine metabolism (13), 
which diminishes responsiveness to behavioral interventions and NRT (14, 15).  Bupropion, by 
contrast, is efficacious for smoking cessation in fast metabolizers of nicotine (15).  Second, 
although precise statistics are not yet available on the frequency with which bupropion is 
prescribed to pregnant women, it was the fourth most commonly prescribed antidepressant in 
pregnancy in 2007 (16).  Moreover, bupropion in combination with cognitive behavioral therapy 
appears to promote greater smoking cessation rates and a longer time to relapse than placebo 
among women with smoking-related weight concerns (50), a potential contributing factor to 
smoking and relapse in postpartum smokers, including lower SES women (51).  Further, 
depressive symptoms are common in pregnant women and are linked to continued smoking and 
data suggest that depressed smokers may respond better to bupropion than non-depressed 
smokers (52). Finally, bupropion appears to be safer than NRT for use in pregnancy.  De Long 
et al. (53) examined the effect of fetal and neonatal exposure to bupropion on postnatal 
metabolic and reproductive outcomes in rats.  In contrast to fetal exposure to nicotine (54), 
exposure to bupropion did not adversely affect metabolic outcomes or the fertility of the female 
offspring. Lastly, a small, preliminary study (55) showed that bupropion reduced CPD and 
improved mood among pregnant smokers more than citalopram/escitalopram. 
Behavioral interventions for smoking cessation in pregnant women are of limited efficacy, failing 
to adequately address several factors that are particularly relevant to smoking in this population 
(e.g., depression, rate of nicotine metabolism). Of the first-line medications, NRT has shown 
limited efficacy in pregnant smokers and in animal models of fetal exposure show a number of 


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associated potential adverse effects on offspring.  Although varenicline is efficacious in non-
pregnant smokers, there are no safety data on its use in pregnancy.  Bupropion is efficacious in 
non-pregnant smokers, is less likely to cause adverse fetal effects than nicotine, and is 
efficacious in fast metabolizers of nicotine and smokers with depressive symptoms and weight 
concerns (all factors that are common during pregnancy).  Thus, we propose to conduct the first 
adequately powered RCT of bupropion to treat ND in women who continue to smoke during the 
second trimester of pregnancy.   
The choice of dosage is based on the widely used dosage for smoking cessation, which is 
initiated at 150 mg/day with a subsequent increase to 300 mg/day (150 mg twice daily). 
 
Potential Risks 
The most common adverse events associated with bupropion when used for smoking cessation 
are dry mouth (11%), insomnia (31%) and dizziness (8%).  
 
Frequent adverse reactions (occurring in at least 1% of patients) include rhinitis, neck pain, 
allergic reaction, hot flashes, hypertension, increased appetite, anorexia, constipation, 
arthralgia, myalgia, tremor, somnolence, thinking abnormality, bronchitis, pruritis, rash, dry skin, 
urticaria, taste perversion, asthenia, fever, headache, dyspepsia, vomiting, agitation, 
depression, irritability sweating, blurred vision or diplopia, and urinary frequency (Zyban 
Package Insert). 
 
 
Infrequent adverse reactions (occurring in less than 1% but greater than 0.1% of patients) 
include: chills, inguinal hernia, photosensitivity, flushing, migraine, postural hypotension, stroke, 
tachycardia, vasodilation, abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, 
jaundice, stomatitis, ecchymosis, edema and peripheral edema, leg cramps and twitching, 
abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, 
depersonalization, emotional lability, hostility, hyperkinesia, parkinsonism, hypertonia, 
hypesthesia, paresthesia, suicidal ideation, and vertigo, accommodation abnormality and dry 
eye, polyuria, and urinary urgency (Zyban Package Insert). 
 
Rare adverse reactions (occurring in less than 0.1% of patients) include: malaise, syncope, 
amnesia, ataxia, derealization, hypomania, and bronchospasm (Zyban Package Insert). 
 
Bupropion is contraindicated in patients with a history of seizure disorder or in patients with a 
current or prior diagnosis of bulimia or anorexia, because of a higher incidence of seizures in 
these individuals when treated with bupropion. 
Patients taking bupropion for smoking cessation have experienced mood changes, including 
depression or mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, 
hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, 
and completed suicide. 
Abuse potential:   Bupropion is not likely to be reinforcing to users of stimulants, including 
amphetamines. Abuse of bupropion by inhalation or injection of crushed tablets have been 
reported, resulting in seizures and/or death. 
The risk of bupropion for smoking cessation in pregnant women has not been adequately 
evaluated. There is a risk that bupropion could adversely affect the developing fetus. 
 
Potential Benefits 
Several medications are FDA approved for smoking cessation in non-pregnant smokers.  


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Nicotine replacement therapies (NRTs) partially replace the nicotine usually derived from 
smoking, relieving craving and other withdrawal symptoms (39, 40).  The odds ratio (OR) of 
abstinence with NRTs compared to placebo varies from 1.5 for the nicotine gum to 2.3 for the 
nasal spray (12).  Bupropion has an OR of 2.1 for smoking cessation (12) and has been shown 
to reduce depressive symptoms in smokers (42), particularly smokers with high baseline 
depression (52). Varenicline, an α4β2 nicotinic receptor partial agonist (44), has an OR of 3.1 in 
promoting smoking cessation (12).  However, there are no safety data on the use of varenicline 
for pregnant smokers.  As discussed below, bupropion may be especially efficacious for 
smoking cessation in pregnant women.  
 
Studies of NRT for Smoking Cessation during Pregnancy 
In an effectiveness study (45), pregnant smokers received cognitive-behavioral therapy (CBT) 
and were randomly assigned to receive a choice of NRT (gum, patch, or lozenge) or no 
medication. Although the quit rate in the NRT group was approximately double that of the 
comparison group, the study was stopped because the NRT group had twice the serious 
adverse event (SAE) rate of the no-medication group.  After adjusting for a history of preterm 
delivery, which was the most common SAE, the difference in SAE rate between groups was not 
statistically significant (p=0.09). Three efficacy studies of NRT have been conducted in pregnant 
smokers (46-48). In a Danish study (46), all women received counseling and either 6 weeks of a 
nicotine patch or placebo.  At the end of pregnancy, neither quit rates nor mean CPD differed by 
group.  However, patch compliance was poor (i.e., the average use being only 2 weeks).  In a 
US study (47), 194 pregnant smokers were randomly assigned to receive treatment with 2 mg 
gum or placebo combined with individual behavioral counseling. Smoking cessation rates were 
non-significantly higher in the NRT group.  Importantly, despite limited adherence to NRT, it 
produced a greater reduction in CPD and cotinine concentrations than placebo and was 
associated with better treatment retention.  Mean (SD) birth weight [3287 g (SD=569) vs. 2950 g 
(SD=657); p<0.001] and mean gestational age [38.9 weeks (SD=1.7) vs. 38.0 weeks (SD=3.3); 
p=0.014] were significantly greater in the nicotine group.  In a UK study (48), 1,050 pregnant 
smokers were randomly assigned to nicotine patch or placebo for 8 weeks, combined with 
behavioral counseling.  Although the quit rate was higher at 1 month in the NRT group (21.3% 
vs. 11.7% for placebo), the rate of abstinence from the quit date until delivery did not differ 
significantly (9.4% for NRT and 7.6% for placebo).  Importantly, however, adherence was very 
low.  Thus, NRT does not enhance quit rates in pregnant women, possibly due to the higher rate 
of metabolism (i.e., inactivation) of nicotine in pregnancy and poor medication adherence in the 
studies. 
 
Risk-Benefit Ratio 
As described above, there are several reasons to evaluate bupropion in the treatment of 
pregnant smokers, who along with their offspring are at substantial risk from smoking.  Despite 
an absence of safety data for bupropion use in pregnancy, preclinical data show that, 
particularly during the second trimester of pregnancy, the medication has not been associated 
with substantial risk of adverse effects on the fetus.  As a consequence, obstetricians often 
choose bupropion to treat depression in pregnant patients.  Based on the substantial potential 
risk and limited risk of adverse effects, the risk-benefit ratio for the proposed study appears to 
be positive. 
2. Study Objectives 
Specific Aim 1:  Conduct a 10-week placebo-controlled trial of bupropion 300 mg/day in 360 
pregnant smokers who are at 13–26 weeks gestation.  We will monitor smoking behavior and 
adverse effects (AEs) of the medication during a 10-week treatment period, with follow up for 


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the remainder of the pregnancy (measuring length of gestation, rate of pregnancy 
complications, and birth outcomes).  We will also provide two booster counseling sessions at 
weeks 2 and 6 postpartum and a final research evaluation at 24 weeks post-TQD.  We will use 
text messages to send pregnancy-relevant information and medication-adherence cues based 
on their demonstrated ability to improve adherence in various populations (e.g., 22, 23).  We 
hypothesize that: 
H1: Bupropion-treated women will have a greater rate of biochemically confirmed cigarette 
abstinence than placebo-treated women.  
H2: There will be no significant differences between treatment arms in the frequency of 
severe treatment-related AEs. 
H3: Bupropion treatment will result in a higher birth weight than placebo. 
 
Specific Aim 2:  Assess changes in depression symptoms and craving as mediators of 
bupropion’s effect on quit rates.  
 
Exploratory Aim:  Explore genetic, metabolic, and social/behavioral moderators of the efficacy 
of bupropion on cigarette abstinence and safety. To generate new hypotheses, we will explore 
whether the risk of AEs and the efficacy of bupropion treatment (vs. placebo) is moderated by: 
1) the rate of nicotine metabolism (i.e., nicotine metabolite ratio (NMR)] and variation in 
CYP2A6; 2) variation in CYP2B6 and plasma concentrations of bupropion and 
hydroxybupropion; and 3) variation in social/behavioral variables, including weight concerns, 
body image, and the presence of other smokers in the home. 
3. Study Design 
3.1   General Design 
Phase II Study - This is a phase II, prospective, placebo-controlled RCT of the efficacy and 
safety of bupropion in combination with behavioral counseling for smoking cessation during 
pregnancy (see Fig. 1).  Pregnant smokers (N=360) will receive bupropion or placebo treatment 
for 10 weeks, under strict double-blind conditions, with 3 post-treatment follow-up sessions: 2 
and 6 weeks postpartum (with counseling to prevent relapse or encourage a repeat quit 
attempt) and monitoring of the persistence of treatment effects at 24 weeks post-TQD.  
 
Study Duration – The duration of the treatment will be 10 weeks with 3 post-treatment follow-
up visits: 2 weeks and 6 weeks postpartum and 24 weeks post-TQD. Birth outcomes will be 
obtained from labor and delivery records (permission for which will be included in the informed 
consent form).  The entire study will run for approximately 54 months from the first participant 
enrolled to the last participant assessed at 24 weeks post TQD. 
 
3.2  Primary Study Endpoints 


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• 
Primary smoking status will be assessed using the Timeline Follow-back method (165) and 
by using carbon monoxide (CO) concentration to biochemically verify the self-report.  
Participants will be considered to be abstinent if they self-report abstinence (not even a puff 
of a cigarette) for >7 days prior to the assessment after 10 weeks of treatment and at 24 
weeks post-TQD and have a CO <10 ppm at that time (166-167). As per convention, 
participants are assumed to be smoking if they self-report to be smoking at the time point, 
cannot be reached to provide data at the time point, fail to provide a breath sample at the 
time point, or provide a breath sample at the time point that has a CO concentration >10 
ppm (166).  
 
• 
For adverse effects, our primary outcome will be the frequency of moderate or severe side 
effects from a checklist of bupropion-related side effects (derived from completed bupropion 
studies), as well as those elicited with open-ended questions, through regular obstetrics visits, 
and assessments triggered by any pregnancy-related complication.  Adverse effects will be 
systematically assessed by study personnel at 5 time points over the course of the 10-week 
study and can trigger dose reductions or suspension of medication.  
  
• 
Birth outcomes obtained from labor and delivery records (permission for which will be 
included in the informed consent form) will include gestational age, overall and spontaneous 
preterm birth (i.e., at less than 37 weeks), infant birth weight, whether small for gestational 
age (i.e., <10th percentile birth weight for gestational age as determined by the Alexander 
curve), head circumference, Apgar scores, and NICU admissions.  Obstetric complications 
will include type of delivery and delivery and postpartum complications.   
3.3  Secondary Study Endpoints 
Secondary smoking cessation outcomes include: smoking rate after 10 weeks of treatment 
and at 24 weeks post-TQD for non-abstainers, prolonged abstinence to weeks 10 and 24 
Placebo
(n = 180)
R
Bupropion
(n = 180)
Follow-up
Follow-up
Weeks
Bupropion + Counseling
-1     0   1      3    5     7            
10* 
24*              PP**         PP*
ASSESSMENTS/COUNSELING
Weeks
BSL = Baseline (and Intake Session and Randomization); A = Assessment; C = Counseling; TQD = Target Quit Day; ^
Corresponds to blood draw for NMR (week -1) and for assessment of bupropion and bupropion metabolites to
assess adherence; * Corresponds to End-of-Treatment and 6-months post-TQD and primary outcomes; ** Two
additional brief counseling/assessment sessions will be provided at 2- and 6-weeks postpartum (PP).
Placebo + Counseling
BSL
BSL
-1^  0     1     3      5^     7                            10                                24          WK2 PP  WK6 PP
A    A,C   A,C A,C A,C
A         
A
A
A,C              A,C
Figure 1
TQD
WK2        WK6


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(defined below), continuous abstinence at weeks 10 and 24 (defined below), time to 7-day 
relapse (no grace period), and lapse and recovery events.  
 
3.4 Safety Endpoints 
 
Participants with severe psychological symptoms (e.g., suicidal thoughts), experiencing a 
serious adverse event that the Principal Investigator believes to be related to study drug and 
a potential threat to the health and safety of the participant or fetus will be withdrawn from 
the study (see section 8.1). 
4.  
Participant Selection and Withdrawal 
 4.1. Inclusion Criteria 
1. Currently smoking on average 3 or more cigarettes per day for the preceding 7 days with 
a breath CO of at least 5 ppm and wants to quit smoking 
2. Pregnant at 13-26 weeks gestation (to maximize safety and the likelihood of receiving 10 
weeks of treatment) 
3. >18 years of age 
4. Able to speak and read English at a 6th grade level or higher, using the Slosson Oral 
Reading Test (SORT) 
5. Committed to remaining in the geographic area for at least 3 months postpartum  
6. Able to sign written informed consent and commit to completing the procedures involved 
in the study. 
7. Methadone or buprenorphine-maintained women must be in methadone or buprenorphine 
treatment for a minimum of 2 weeks prior to entering the study.  Their 2 most recent urine 
drug screens, consecutive and administered at least one week apart, must both be 
positive for methadone or buprenorphine and negative for drugs of abuse other than 
cannabis. Participants who screen positive for other drugs at either time point will not be 
enrolled in the study until they meet this criterion. 
 
 
4.2. Exclusion Criteria 
1. During the last 90 days from screening visit, meets any criteria for a DSM-IV diagnosis of 
drug or alcohol dependence—excluding tobacco or cannabis dependence and, for 
methadone or buprenorphine maintenance patients, opioid dependence—AND either 
evidences ongoing use of illicit drugs other than cannabis or continues to abuse or 
misuse prescription drugs such as CNS stimulants. 
2. Pregnant with triplets or higher order multiples  
3. Has an unstable psychiatric disorder (i.e., suicide risk moderate or severe, as reflected 
by a score of >9 on the MINI Section B (Suicidality) or a suicide attempt during the 
preceding year, psychiatric hospitalization within the last 3 months; current psychotic 
disorder based on the MINI) 
4. Current or past Bipolar Disorder as determined by a study psychiatrist or psychologist 
based on assessment with the MINI,  relevant information from the medical record and, 
when warranted, direct clinical evaluation.  
5. Current, regular use of psychotropic medication, inhibitors of CYP2B6 (e.g., ticlopidine,     
clopidogrel), inducers of CYP2B6 (e.g., ritonavir, lopinavir, efavirenz), anticonvulsants 
(e.g., carbamazepine, phenobarbital, phenytoin), beta-blockers (e.g., metoprolol), Type 
1C antiarrhythmics (e.g., propafenone and flecainide), drugs that require metabolic 
activation by CYP2D6 to be effective (e.g., tamoxifen), drugs that lower seizure 


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threshold (e.g., antipsychotics, tricyclic antidepressants, theophylline, or systemic 
corticosteroids), levodopa or amantadine 
6. 
Current unstable medical problems or potential inability to tolerate study treatment [e.g., 
threatened abortion: current persistent hyperemesis gravidarum (HEG) requiring 
intravenous fluids (to be rescreened when HEG is stabilized/resolved and no electrolyte 
abnormalities are evident); hypertension with evidence of end organ dysfunction or on 
more than 2 medications at the start of the pregnancy]; arteriovenous malformation; 
AIDS;  laboratory evidence of hepatic impairment (e.g. viral hepatitis with serum 
transaminase levels more than twice the upper limit of normal) ; renal impairment (e.g., 
elevated creatinine or creatinine clearance <75cc/hr), metabolic disorders (e.g., 
hypoglycemia, hyponatremia) or end organ damage from any chronic medical condition 
(e.g. abnormal pulmonary function tests), glaucoma,  or other significant medical 
problems that in the opinion of a study obstetrician makes the risk of study participation 
unacceptable. 
7. Known major fetal congenital malformation—as determined by the study obstetrician—
diagnosed prior to study randomization 
8. History of seizure disorder 
9. Current use of a smoking cessation medication in addition to the study medication, such 
as nicotine replacement therapy  
10. Current or history of bulimia or anorexia nervosa 
11. Current use of tobacco products other than cigarettes (e.g., E-cigarettes) 
12. Current clinically significantly abnormal laboratory evaluations that are not adequately 
controlled by standard of care treatment.     
13. History of severe head injury (i.e., with loss of consciousness) 
14. Any medical condition or concomitant medication that could compromise subject safety 
or treatment, as determined by the Principal Investigator and/or Study Physician. 
15. Inability to provide informed consent or judged by the Principal Investigator and/or Study 
Physician to be an unsuitable candidate for a clinical drug trial. 
4.3. Participant Recruitment and Screening 
All sites will have a senior clinician to oversee the integration of the trial into clinical practice. 
Approval from the City of Philadelphia Institutional Review Board and the Health 
Commissioner’s Office will be obtained given the involvement of Philadelphia Department of 
Public Health data, staff, and clients at the Jefferson MATER site, where methadone-maintained 
pregnant smokers will be enrolled.  Buprenorphine-treated subjects will be recruited from the 
“Mothers MATTER” program at the Dickens clinic and from the Jefferson MATER site. As in our 
previous successful clinical trials (e.g., 14, 47, 52), we will use experienced and trained 
research staff to identify and screen potentially eligible participants in the clinics. Recruitment 
sites will also be provided with IRB-approved materials designed to raise awareness of the 
study, including posters and brochures to be displayed prominently in all clinic areas.  We will 
also encourage referrals from clinicians in the surrounding areas at each site, and will recruit 
through newspapers, maternity magazines and social media.  Interested and potentially eligible 
participants will be scheduled for an intake session (week -1) to determine eligibility. For details 
on Screening, see 6.2 Informed Consent and Screening Visit below. 
4.4.   Early Withdrawal of Participants 
    4.4.1. When and How to Withdraw Participants 
Participants with severe psychological symptoms (e.g., suicidal thoughts), those who fail to 
adhere to protocol requirements, and those who withdraw consent will be withdrawn from the 


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study and if applicable, referred for appropriate clinical care. Any participant experiencing a 
serious adverse event that the Principal Investigator believes to be related to study drug and a 
potential threat to the health and safety of the participant or fetus will be withdrawn from the 
study (see section 8.1). 
    4.4.2. Data Collection and Follow-up for Withdrawn Participants 
We will make a strong effort (via phone calls and alternative contact information) to obtain 
follow-up information on all participants who are prematurely withdrawn from the project. 
5. Study Drug  
Bupropion is an antidepressant medication for oral administration approved in the United States 
for the treatment of Major Depressive Disorder, Seasonal Affective Disorder and Smoking 
Cessation in adults. For more detailed information, see section 1.2 (Investigational Agent). 
5.1.  Description 
Bupropion for this study is supplied as commercial SR 150mg tablets. The placebo will be supplied 
as over-the-counter calcium carbonate 648mg tablets which are nearly identical in size, shape 
and color to the active bupropion product. 
5.2.  Treatment Regimen 
Participants will be randomized to receive Bupropion or placebo, to begin after completing the 
Baseline visit according to the regimen in Table 1 below. 
5.3. 
Method for Assigning Participants to Treatment Groups 
Participants will be randomly assigned to one of two treatment conditions: Bupropion 300 
mg/day (n = 180) or placebo (n = 180). We will use small-block randomization by site (Penn or 
MATER) provided by Dr. Lynch, the study biostatistician.  A PHQ-9 score of 10 or greater will be 
used to identify major depression and stratify the randomization on it. Study site (Penn or 
MATER) will be the second of the two stratification variables.  Study staff and the Investigational 
Drug Service (IDS) staff will be responsible for medication randomization.  The process for 
randomization is: 1) The research coordinator will complete a “randomization form,” which 
includes the variables to be entered into the randomization program and fax or email the form 
without protected health information to the UPenn site; 2) A designated study staff member 
 
Table 1: Medication Dispensing Schedule 
 
Medication 
Dispensed For 
Morning Dose 
Evening Dose 
Total Daily 
Dose 
Visit A: Screening  
N/A 
No medication 
No medication 
 
Visit B: Baseline 
Wk 1 
150 mg 
No medication (for 
first 3 days); then 
150 mg 
150 mg 
Visit C: Wk 1  
Wk 2 through Wk 5 
150 mg 
150 mg 
300 mg 
Visit D: Wk 3 
N/A 
N/A 
N/A 
N/A 
Visit E: Wk 5 
Wk 6 through Wk 
10 
150 mg 
150 mg 
300 mg 
Visit F: Wk 7 
 
150 mg 
150 mg 
300 mg 
Visit G: Wk 10 
Endpoint 
No medication 
No medication 
N/A 


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Visit H: Wk 24 
Post-TQD 
N/A 
No medication 
No medication 
N/A 
Visit I: 2 wk 
postpartum 
N/A 
No medication 
No medication 
N/A 
Visit J: 6 wk 
postpartum 
N/A 
No medication 
No medication 
N/A 
at the UPenn site will enter the variables into the randomization program, which will assign a 
randomization group to the participant; 3) the designated study staff member will fax the 
participant’s randomization group to IDS, which will assign a kit number to the participant and 
fax the kit assignment to the research coordinator; 4) the research nurse or physician will 
dispense medication to the participant and complete and sign the IDS prescription form included 
in the starter kit; 5) The research coordinator will fax the completed form to IDS. The medication 
will be dispensed using the above dosing schedule. To maintain double-blind conditions, study 
staff responsible for randomization will not be involved in the recruitment of participants, study 
visits, or data collection. IDS will provide each study site a supply of starter kits to use for initial 
study medication dispensing.  
 
Study drug for subsequent visits will be ordered by the research coordinator using the 
“Research Pharmacy Schedule” form, a copy of which will be retained in the participant’s 
research file.  The study drug will be ordered at Baseline Visit B for Weeks 2-5 and Target Quit 
Day Visit C for Weeks 6-10. The study drug will be picked up at IDS and brought to the study 
visit. If the participant is unable to attend the scheduled study visit the study drug will be stored 
at the Treatment Research Center in the Medication Room. Study drug will be dispensed at 
three time points during the study: Baseline (Visit B: 1 week of medication), Target Quit Date 
(Visit C: 4 weeks of medication), and Week 5 (Visit E: 5 weeks of medication). The initial 
dispensing will be done directly by the research nurse or physician, who will ensure that the 
patient understands the medication regimen. Study medication will be dispensed by the 
research nurse, physician, or research coordinator (trained and supervised by the nurse or 
physician), who will assess each participant for study medication AEs, documenting and 
reporting them as required. Participants with severe psychological symptoms or determined to 
be inappropriate for the study by an investigator will be withdrawn from the study.  A study nurse 
or physician will follow participants withdrawn completely from treatment until they are referred 
for appropriate clinical care.  For research purposes, and with the participant’s continued 
approval, we will collect data at all subsequent time points until the 24 weeks post-TQD visit. 
5.4. 
Preparation and Administration of Study Drug 
     5.4.1 Chemistry and Manufacturing: Bupropion sustained-release 150mg tablets will be 
purchased commercially, as round white tablets with only an imprint.  An over- the-counter 
calcium supplement in tablet form, with similar shape and color, will be used as the ‘placebo’ for 
bupropion tablets in this clinical trial. Medication will be prepared at the University of 
Pennsylvania, Investigational Drug Service, 3600 Spruce Street, Ground floor Maloney Building, 
Philadelphia, PA 19104.      
5.4.2 General Method of Preparation and Packaging:  The Investigational Drug Service will 
purchase Bupropion sustained-release 150mg tablets (made by Watson Laboratories) from a 
pharmaceutical wholesaler.  These tablets were selected because they are round, white and have 
an imprint on only one side of the tablet. 
The tablets will be used without alteration.  For dispensing to study participants, they will be 
packaged in blister cards with the imprint facing the foil, so that members of the research team 
cannot see the imprint side of the tablet. 


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     5.4.3  Drug Components and Drug Product:  The finished drug product will consist of the 
following components: 
   
a.  Bupropion sustained release 150mg tablet.  Source:  Watson Laboratories (NDC# 
00591-0839-XX) 
b.  Placebo Product:  For the purpose of conducting this clinical trial, an over the counter 
supplement with similar appearance to the active bupropion tablet, will be used as the placebo 
control.  The tablet will be used unaltered.  For purposes of maintaining the study blind, tablets 
will be dispensed in a blister card, with the imprint facing the foil, so that members of the 
research team cannot see the imprint side of the tablet.  The finished drug product will consist of 
the following components:  Calcium Carbonate, 648mg.  Source: Major Pharmaceuticals (NDC# 
00536-3414-10) 
 
c.  Labeling:  The following label will be placed on the blister card at time of dispensing 
to a study participant: 
 
Caution: New Drug Limited by 
Federal (USA) Law to 
Investigational Use Only 
          University of Pennsylvania – Investigational Drug Service 
            3600 Spruce Street – Ground Maloney – Philadelphia PA 
19104    215-349-8817 
 
RX # XXXXXXXXX                           Dr. _________________ 
Patient: XXXXXX (######)               Date: ________ 
TAKE ONE (1) TABLET BY MOUTH EACH DAY AS 
DIRECTED. 
IND# ######     Study Period: ____     
BUPROPION SR 150 MG OR PLACEBO TABLETS #9 
Study #######         Refills: 0 
INVESTIGATIONAL DRUG 
[BARCODE HERE] 
Rx# XXXXXXXXX 
 
 
d.  Environmental Analysis Requirements;  Given the planned use of the investigational 
agent in this study, we believe an environmental analysis is not required. 
     5.4.4 Provide study medication to study sites IDS will provide study medication for the 
MATER, Jefferson and Penn study sites.  Treatment will last for 10 weeks and medication will 
be dispensed in 4 increments: At baseline, participants will receive medication for week 1; at 
week 1, they will receive medication for weeks 2 through 5; and at week 5 for weeks 6 through 
10. IDS will provide each study site a supply of starter kits to use for initial study medication 
dispensing. Study medication will be stored at room temperature (59-86º F) in a locked drawer 
in the TRC study medication storage room. The room is monitored daily for temperatures and 
has limited study staff access. The study medication will be stored until dispensed by the nurse 
or study coordinator for distribution to participants.  
 
5.5   Participant Compliance Monitoring 
We will conduct tablet counts at each in-person visit for all study participants. Unused amounts 
will be documented. Proper drug dosing will be reviewed with participants at each visit with clear 
instructions to take all study tablets as directed. Study coordinators at each clinical site will 
maintain a tracking log of all study medication ordered from IDS, dispensed to participants, 
returned by participants and then returned to IDS. Coordinators will return study medication 
blister packs and unused study medication to IDS after each participant completes the last 
follow-up visit.   


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5.6   Packaging 
The Investigational Drug Service of the University (IDS) of Pennsylvania will package bulk drug 
on-site, containing medication in blister packaging.  Medication will be dispensed in amounts as 
described in Study Procedures (below). 
5.7   Blinding of Study Drug 
All participants and research staff will be blinded as to whether the participant is in the 
bupropion or placebo group until the end of the study once the decision to break the study blind 
is determined (after study database lock). Codes linking randomization number for each 
participant to actual treatment will be secured in a sealed, opaque envelope and maintained in a 
locked drawer in the research pharmacy and the hospital pharmacy. Research participants will 
be given the emergency contact number for the study during the consenting process. 
See section 8.4 (Unblinding Procedures) for a description of the process for unblinding a study 
participant. 
6. Study Procedures 
6.1 Recruitment 
We will distribute IRB-approved recruitment materials (i.e. brochures, post cards and posters) to 
recruit women who smoke and wish to quit smoking through participation in the trial.  We will 
work with Jefferson and Penn OB clinics to access EPIC to identify pregnant smokers receiving 
prenatal care and, working with their obstetrician, invite them to consider study participation.  
We will ask clinicians for permission to mail IRB-approved recruitment materials to their 
patients, who have reported recent smoking behavior and may meet study inclusion criteria 
based on EPIC screening. We will also advertise in media, including online classifieds such as 
Craigslist, newspapers (print and online), magazines, radio, and social media. We will use 
Facebook and Instagram to post study recruitment ads, including pictures and texts.  Interested 
individuals can click a link that will redirect them to the recruitment landing page. The landing 
page will ask interested participants to fill in information—including name, phone number, 
pregnancy status and smoking status—to determine whether they are eligible.  The landing 
page will be housed on a secure web server that is encrypted and password protected with 
different levels of user access and privileges. The web server—our Data Management Unit 
(DMU)—is flexible and ensures data quality and security (see appendix).  
 
 
 
 
 


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We will post and distribute recruitment material in community settings with public posting areas 
or other means of providing community access to materials (such as town halls, public libraries, 
YMCAs, health fairs). We will obtain permission at select locations before distributing or posting 
the approved recruitment materials (ensuring compliance with other institutions guidelines, 
including seeking IRB approval as needed to conduct recruitment activities). We will also 
encourage referrals from clinicians in the surrounding areas at each site including Penn Family 
Medicine. At the Jefferson site, we will recruit patients from MATER (Maternal Addiction, 
Treatment, Education and Research, which provides methadone maintenance treatment for 
pregnant women), part of the Pediatrics Department. MATER is located at 1233 Locust Street, 
4th floor, Philadelphia, PA 19107, which is where recruitment will take place and treatment will 
be delivered.  We will also recruit patients from Jefferson University Department of Obstetrics 
and Gynecology Associates (JOGA).We will conduct a brief in-person pre-screening 
questionnaire and a screening interview over the phone or in-person at the participant’s 
obstetrics clinic to assess study eligibility criteria. At Jefferson, medical records will be reviewed 
for gestational age and smoking status to identify prospective participants.  Prospective 
participants who appear to meet eligibility criteria for the study will be scheduled for an in-person 
Informed Consent and Screening visit. See Table 2 below for the schedule of assessments. 
Buprenorphine-treated women will be recruited through the Penn and Jefferson MATER sites as 
described above. 


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6.2 Visit A: Informed Consent and Screening (Approximately 60 minutes, in- 
person)  
In a private setting, each participant will receive a description by a study staff member of the 
study protocol, its risks, potential benefits, and alternative treatments available.  Following 
resolution of any questions, participants who appear to understand the nature of the study and 
consent will be asked to sign the study consent form. We have created two informed consent 
forms (ICFs), one for Penn and one for Jefferson, to address site-specific differences. An entire 
copy of the ICF will be given to each participant, who will be reminded that the consent 
expresses her willingness to participate but that the subsequent screening process will 
determine final eligibility. Further, she will be reminded that participation is voluntary, and at any 
time, she may withdraw from the study. Following the informed consent process, a research 
coordinator will obtain demographic information, administer a reading test (SORT), and extract 
information from the patient’s medical record (including medical history and medications, 
obstetric history, blood pressure, and weight), and perform a psychiatric diagnostic interview 
(MINI; sections A through K) the PHQ-9 to differentiate depressed and non-depressed women  
for randomization, and a Timeline Follow-back smoking interview covering the preceding 30 
days. We will also measure breath CO at this and every subsequent visit. 
The participant will also be asked to provide locator information. Selection of follow-up locators 
is particularly important for the successful tracking of patients for follow-up evaluations.  Study 
staff will select patient locators on the basis of relationship to client, duration and current status 
of relationship, frequency of contact with the patient, and willingness to participate.  Locators are 
contacted when efforts to reach a patient are unsuccessful, which contributes both to 
maintaining patients in treatment and enhancing data collection. Participants will be asked for 
one or two locators.  
The initial assessment in the clinic will help to exclude ineligible participants, facilitate clearance 
by an obstetrician for any medical condition that requires approval (e.g., mild hypertension), and 
ensure that the woman’s gestational age is 13-26 weeks. Gestational age will be assessed for 
enrollment purposes based on the method used by the NICHD-sponsored Maternal-Fetal 
Medicine Units Network.  The gestational age will be based on the projected estimated date of 
delivery (EDD), as determined by U/S and the last menstrual period (LMP;see below).  Because 
the project EDD depends on information from the earliest dating U/S, if no U/S has been 
performed previously, one will be performed to determine eligibility. The EDD also requires that 
the first day of the LMP be determined and a judgment made as to whether or not the 
participant has a “sure” LMP. 
• 
If the LMP date is uncertain, the U/S measurements obtained at the participant’s first U/S will be 
used to determine the projected gestational age, by the standard method used at the 
recruitment site. 
• 
If the date of the LMP is certain and the U/S confirms the gestational age within +/- 7 days, the 
LMP-derived gestational age will be used to determine the project gestational age. 
• 
If the U/S-determined gestational age does not confirm the LMP-generated gestational age 
within +/- 7 days, the U/S will be used to generate the project gestational age. 
Thus, all participants will be assigned a project EDD and gestational age when they are 
evaluated for enrollment.  An U/S machine is available at each recruitment site and results will 
be supervised and reviewed by Dr. Srinivas (Penn) or Dr. Jason Baxter, M.D. (Jeff). 


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6.3 Visit B: Baseline (Pre-quit) (Approximately 90 minutes, in-person or divided 
between in-person and telephone sessions) 
Although this session requires an in-person visit, part of the session may be completed via 
telephone.  The session must be completed 1-30 days after completion of the screening visit.  
At the in-person visit, we will measure breath CO level and draw three tubes (i.e., 21 cc) of 
maternal blood to assess NMR and provide DNA for genotyping.  Blood will be stored in a 
coded manner in a designated -80° freezer and shipped on dry ice to the laboratory of Dr. 
Rachel Tyndale at the University of Toronto approximately every four months throughout the 
study. Samples from both sites will be shipped from their storage location at Penn (see section 
9.5) and will follow the guidelines for shipping international biological samples as required by the 
university.  
 
Table 2: Study Assessments 
 
Visit A  
Visit B 
Visit C 
Visit D  
Visit E  
Visit F  
Visit G  
 Visit H  
 Visit I  
 Visit J  
 
Screen 
Baseline 
(Pre-quit) 
Wk 1 
(TQD) 
Wk 3 
Wk 5 
Wk 7 
Wk 10 
Wk 24 
Wk 2 
PP 
Wk 6 
PP 
ICF with HIPAA 
X 
 
 
 
 
 
 
 
 
 
Medical record 
review  
C 
 
 
 
 
 
 
 
 
 
Med History 
Questionnaire  
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
SORT 
X 
 
 
 
 
 
 
 
 
 
MINI1 
X 
 
 
 
X2 
 
X2 
 
 
 
TLFB (preceding 
30 days) 
X 
 
 
 
 
 
 
 
 
 
Gestational Age  
X, C 
 
 
 
 
 
 
 
 
 
Blood sample: 
DNA, NMR 
 
X 
 
 
 
 
 
 
 
 
Breath CO* 
X 
X 
X 
 
X 
 
X 
X3 
 
 
Dispense 
medication 
 
X 
X 
 
X 
 
 
 
 
 
Text messaging 
 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
 
 
 
Assessment of AEs 
and medication 
adherence 
 
X 
X  
T 
X  
T 
X 
 
 
 
Weight, blood 
pressure 
X or C 
C 
C 
C 
C 
C 
C 
 
 
 
Pulse 
 
X 
X 
 
X 
 
X 
 
 
 
ACE questionnaire 
 
X or T   
 
 
 
 
 
 
 
 
Smoking History 
Questionnaire 
 
X or T 
 
 
 
 
 
 
 
 
FTND 
 
X or T 
 
 
 
 
 
 
 
 
BISS 
 
X or T 
 
 
 
 
 
 
 
 
WEAQ 
 
X or T 
 
 
 
 
 
 
 
 
PHQ-9 
x 
X or T 
X  
T 
X  
T 
X  
X  
T 
T 
QSU 
 
X or T 
X  
 
X  
 
X 
 
 
 
MED-Q 
 
 
 
 
 
 
X 
 
 
 
TLFB (since last 
visit) 
 
X or T 
X  
T 
X  
T 
X 
X  
T 
T 


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TQD: target quit date; PP: postpartum; ICF: informed consent form; HIPAA: Health Insurance Portability and Accountability Act; 
Assessments: X=in-person; X1=MINI sections A through K will be administered.  X2=Only MINI section B (Suicidality) will be administered; 
X3=in-person only; T=by telephone; C=chart review; SORT: Slosson Oral Reading Test; MINI: Mini-International Neuropsychiatric 
Interview; TLFB: Timeline Follow-back Interview for cigarettes smoked; NMR: nicotine-metabolite ratio; [CO]: carbon monoxide 
concentration; AEs: adverse events FTND: Fagerstrom Test for Nicotine Dependence; BISS: Body Image State Scale; PHQ-9: Patient 
Health Questionnaire-9; WEAQ: Weight Efficacy After taken Quitting survey; QSU: Questionnaire of Smoking Urges; MED-Q: medication 
group question; *CO readings may also be at the time of delivery and at the time of the post-partum office visit 
An in-person or telephone interview will be used to obtain background information for use as 
potential covariates and to assess the study’s external validity [including smoking history (e.g., age 
at initiation, past use of nicotine treatments, current rate, menthol vs. regular tobacco, presence of 
other smokers in the home), obstetrical history to confirm and augment information obtained from 
review of the medical record (number of pregnancies, pregnancy outcomes), and medical and 
psychiatric history (with current medications extracted from the medical chart).  Sessions in which 
the assessments are conducted by telephone, the telephone interview should be completed prior to 
the in-person visit.   
Nicotine dependence severity will be assessed with the Fagerstrom Test for Nicotine Dependence, a 
validated 6-item measure (144). We will measure depression symptom score using the PHQ-9 (145) 
and will use a score of 10 or more to differentiate depressed and non-depressed women.  This cut 
point will enable us to use depression as a stratification variable and potential mediator.  Craving 
severity, which has been related to long-term cessation in cessation trials (147), will be measured 
with the 10-item brief Questionnaire of Smoking Urges (QSU; 146).  The QSU contains 2 subscales 
(anticipation of reward, relief from negative affect.  
Weight concerns will be measured using the Weight Efficacy After Quitting survey, a 6-item 
validated scale that assesses general and smoking- specific weight concerns (148). We will also use 
the Body Image States Scale (BISS) (149), a 6-item measure of evaluative and affective 
experiences of one’s physical appearance.  Body image may be a more potent moderator of 
smoking cessation treatment effects (and such concerns are particularly relevant in pregnant 
women).  A single item in the smoking history questionnaire will assess the number of smokers in 
the home.  The Adverse Childhood Experiences (ACE) questionnaire, a 10-item self-report measure 
will be administered at this time as well. 
Following the assessments, participants will receive the first session of manual-based counseling 
from a coordinator that is trained and supervised by Dr. Schnoll. The counseling protocol is based 
on Public Health Service guidelines for smoking cessation treatment (12) and is intended to enhance 
study retention and ensure that participants in the placebo arm receive active treatment to quit 
smoking.  The 30-minute, “pre-quit” counseling session will prepare for the target quit day (TQD).  
This session focuses on reviewing the participant’s history and experience with quitting, beliefs 
about smoking and quitting, and perceived barriers to cessation.  The participant will receive a one-
week supply of study medication and the nurse or physician will review with the participant 
instructions for taking the study medication, which include instructing the participant to begin taking 
the medication on the following morning. Study staff will complete a baseline adverse event 
checklist, an open-ended evaluation of any existing symptoms using the established study checklist 
of adverse events, before the subject begins taking the study medication.  
Smoking cessation 
counseling (30 min) 
 
X  
 
 
 
 
 
 
 
 
Smoking cessation 
counseling (20 min) 
 
 
X  
 
 
 
 
 
 
 
Smoking cessation 
counseling (10 min) 
 
 
 
T 
X  
 
 
 
T 
T 
Blood sample: 
[bupropion, 
hydroxybupropion] 
 
 
 
 
X 
 
 
 
 
 
Birth outcome data 
 
 
 
 
 
 
 
C 
 
 


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Upon initiation of the medication, subjects will begin to receive daily text messages describing the 
progress of their pregnancy and reminding them to take their medication.  The text messaging will 
continue throughout the 10-week medication treatment period.  The greatest impact of this approach 
has been seen with interventions that include personalized text message reminders and interactivity 
(105).  Personal tailoring will involve: 1) flexibility in the timing of receipt of messages each day (“set 
time” chosen by the woman) and 2) day-by-day facts, tips, suggestions, and benchmarks 
appropriate to each stage of fetal development calculated using the woman’s estimated date of 
delivery.  The morning message will consist of 2 components: a “hook” text that details the fetus’ 
development and pregnancy tips and a “prompt” text reminding the subject to take her medication at 
the prescribed times.  We will use a database of messages consisting of SMS text and rules to 
determine which message to send based on gestational age, time of day, and the participant’s 
previous replies. An example morning message is: 
Your baby’s heart is now developed. Remember to take your study medication with your 
morning and evening meals.  
  
The evening message will ask participants whether they took their study medication as 
prescribed: 
Did you take the study medication as prescribed today? 
Reply 
"1" for Yes, I took it today 
"2" for No, I did not take it today 
  
If participants do not respond to the evening message within 1 hour, a reminder message will be 
sent (“Did you take your study medication as prescribed today. REPLY "1" for Yes, I took it 
today; "2" for No, I did not take it today.”). A maximum of three text messages will be sent in a 
given day.   
 
All participants will be offered a free cell phone with unlimited talk and text for up to 32 weeks of 
study participation to allow them to receive the text messages, participate in phone counseling 
and to contact study personnel. Participants have the option to refuse the phone. They will be 
asked to return the phone to the study staff at the end of the study. They will be paid $20 for 
returning the phone.  Participants will not be responsible for the cost of lost or stolen phones. 
We will replace a lost or stolen phone once during the study. 
6.4 Visit C: Week 1 (Target Quit Day) (Approximately 45 minutes in person) 
At the in-person visit, we will measure breath CO level and the participant will receive a four-
week supply of study medication.  The nurse or coordinator (trained and supervised by the 
nurse or physician) will review with the participant instructions for taking the study medication 
and record any AEs that the participant may have experienced.  The nurse or coordinator will 
also collect empty medication blister packs and any unused medication.  In-person or by 
telephone, participants will complete the PHQ-9, QSU, will be interviewed with the TLFB, and 
will receive a 20-minute, “quit-day” counseling session to review the initial quit attempt, identify 
potential reasons for relapse, and review a plan to avoid tempting situations.   
 
6.5 Visit D: Week 3 (Approximately 25 minutes by telephone or in person) 
Participants will be asked to complete the PHQ-9 and the TLFB by telephone.  They will then 
receive a 10-minute booster counseling session that focuses on reinforcing success and 
reviewing the quit plan (for participants who have quit smoking) or re-establishing a quit date 


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and restarting the cessation process (for participants who have relapsed to smoking).  The 
counseling schedule reflects the changing needs of the pregnant smoker during the course of 
pregnancy and smoking cessation (155), with more intensive help offered in the earliest phase 
of treatment and continued efforts to prevent relapse in the later stages.  
 
6.6 Visit E: Week 5.  (Approximately 30 minutes in-person) 
At the in-person visit, we will measure breath CO level, and participants will meet with a study 
nurse or coordinator working under the supervision of the nurse or physician to receive a five-
week supply of study medication.  The nurse or coordinator will review with the participant 
instructions for taking the study medication and record any AEs that the participant may have 
experienced.  The nurse or coordinator will also collect empty medication blister packs and any 
unused medication.  Two tubes of blood (14 cc) will be drawn at this visit for shipment to Dr. 
Tyndale’s laboratory at the University of Toronto to measure plasma concentrations of 
bupropion and hydroxybupropion.  Participants will be asked to complete PHQ-9, QSU, and 
TLFB, either in person or by telephone. They will then receive a 10-minute booster counseling 
that focuses on reinforcing success and reviewing the quit plan (for participants who have quit 
smoking) or re-establishing a quit date and restarting the cessation process (for participants 
who have relapsed to smoking).  Suicidal risk will be assessed using the MINI Suicidality section 
(B). 
 
6.7 Visit F: Week 7. (Approximately 15 minutes by telephone or in person)  
Participants will be asked to complete the PHQ-9 and TLFB by telephone.  
 
6.8 Visit G: Week 10 (Endpoint). (Approximately 25 minutes in-person)  
At the in-person visit, we will measure breath CO level.  The nurse or coordinator (trained and 
supervised by the nurse or physician) will review with the participant any AEs that the participant 
may have experienced.  The nurse or coordinator will also collect empty medication blister 
packs and any unused medication.  Participants will be asked to complete the PHQ-9, QSU, 
MED-Q, and TLFB in-person. Suicidal risk will be assessed using the MINI Suicidality section 
(B). 
 
6.9 Visit H: Week 24 Post-TQD Follow-up Visit (Approximately 20 minutes in-
person)  
At the in-person visit, we will measure breath CO level and participants will be asked to 
complete the PHQ-9 and TLFB. Visit may be completed at same time as inpatient hospital visit 
or the outpatient postpartum visit.  
 
6.10 Visits I & J: Postpartum Week 2 and Postpartum Week 6 Visits 
(Approximately 25 minutes by telephone or in person)  
At each visit, participants will be asked to complete the PHQ-9 and TLFB by telephone.  They 
will then receive a 10-minute booster counseling session.  The session will focus on reinforcing 
success and reviewing the quit plan (for participants who have quit smoking) or re-establishing a 
quit date and restarting the cessation process (for participants who have relapsed to smoking).  
Women who have failed to stop smoking or have relapsed will be referred for counseling by staff 
at the obstetrics clinic from which they were recruited and at which they will be receiving early 
postnatal care.   
 


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6.11 Early Termination Visit (Approximately 30 minutes, in-person or divided 
between in-person and telephone sessions) 
Participants who discontinue treatment prematurely will be asked to complete an end-of-
treatment evaluation and all scheduled assessments to facilitate intention-to-treat (ITT) 
analyses.  Participants will be informed of these procedures prior to study enrollment.  
Participants who terminate participation in the treatment prior to Week 10 will also be asked to 
complete the scheduled end-of-treatment (Week 10) procedures.  For this and any other visit 
that cannot be completed in-person, assessments will be conducted by telephone. 
 
6.12 Other Study Procedures and Considerations 
Screening and baseline visits cannot occur on the same day.  The maximum time permitted to 
elapse between completion of the screening visit and completion of the baseline visit is 30 days.  
Every effort will be made to complete visits within a 3-day window before or after the date 
scheduled for the visit as shown in Table 2. However, because the analysis will by intent-to-
treat, we will reasonably accommodate subjects’ time constraints by extending the window as 
needed to complete all study visits. During the week prior to each of the visits (B through J), a 
reminder call will be made to the participant concerning the next scheduled visit.  At the 
reminder call for Visit H (24 weeks post-TQD) the participant will be asked whether she had 
smoked at all during the previous week.  Visit H will be held plus or minus 28 days from the 
scheduled 24 week post-TQD. This large window accommodates changes in delivery dates and 
also allows the visit to coincide with the inpatient delivery or the 6-week post-partum office visit, 
an important convenience for a new mother. If she acknowledges having smoked, an in-person 
visit is not required but may be held.  If she reports no smoking, an in-person visit will be 
conducted to verify self-report using breath CO measurement. Because breath CO is a non-
invasive and simple test, as well as an important outcome measure, we will collect a breath CO 
reading at all in-person opportunities when feasible, including at time of delivery and at the time 
of the 6-week post-partum visit. If the blood draw is unsuccessful at the baseline visit, a second 
attempt will be made at the Week 5 visit. If the second draw is successful, the baseline tubes 
will also be drawn (for all baseline tests if the participant is still smoking or for DNA only if the 
participant is no longer smoking). If the second draw is not successful, we will collect DNA from 
the patient’s saliva using the Oragene Discover Kit (PD-LB-00191). 
 
Monthly protocol adherence meetings will be conducted with the coordinators at each site to 
ensure adherence to the counseling protocol.  All sessions, with permission from the participant, 
will be audiotaped and 15% will be randomly selected for evaluation by Dr. Schnoll using fidelity 
forms to determine adherence to the elements of the counseling, record the duration of the 
session, assess the therapeutic relationship and the coordinators’ attention to the participants’ 
condition, and provide individual feedback and re-training to the coordinators, as needed.  One 
session from each participant will be selected from among the initial, quit day, or booster 
sessions for review.  The standardized checklists will yield a protocol adherence score (from 1 = 
“not at all” to 7 = “extensively”) and inter-rater reliability will be computed following the model of 
Shrout and Fleiss (156).  This process is modeled on previous cessation clinical trials in 
pregnant smokers (157) and the general population of smokers (158), which yielded intraclass 
correlation coefficients of 0.87-0.99. Audio recording is not a requirement of the study and 
participants will be given the opportunity to opt out. Following evaluation, the recordings will be 
deleted electronically. 
 
Throughout the study, if a participant misses a study visit due to a vacation or an unforeseen 
event, study personnel will reschedule the study visit for as soon thereafter as possible. Study 
staff will mail the study medication to the participant via secure mail or courier under the 


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supervision of a study nurse or doctor. Participants will only be provided with enough study 
medication to allow them to maintain their daily dosage of study medication until their next 
scheduled visit.  An investigator will determine how many additional weeks of study medication 
a participant will be allowed to receive without attending a study visit. In extenuating 
circumstances, a home visit may be necessary. In those cases, study staff will utilize public 
transportation (SEPTA), a rental car, or taxi for transportation to and from the visit at the 
subject’s home. 
 
The nurse or coordinator (trained and supervised by the nurse or physician) will provide 
instructions over the phone on how to take the study medication as per the dosing schedule and 
record any adverse events that have occurred since the last study visit. Study nurses or 
coordinators will instruct participants to call our study staff at any time to discuss any problems 
or concerns they may have while taking the study medication.  All participants will be provided 
phone numbers to contact the study staff during office hours and the pager number for off-hours 
contact 24 hours a day. Participants will be asked to come in for their next study visit as soon as 
possible.    
7. Statistical Plan 
7.1. 
Power 
A power analysis is provided only for the primary aims because the exploratory aim is 
hypothesis generating. Most of our power calculations were approximated as 2-sided t- or z-
tests, with α = 0.05, using PASS Software (Power and Sample Size, NCSS Software, Kaysville, 
UT). Equivalence testing was approximated as two one-sided tests, with α = 0.025 each.   
7.1.1. Aim 1: 
The primary efficacy analysis (H1) is a comparison in week 10 (of treatment) and week 24 post-
TQD of CO-confirmed 7-day point prevalence quit rates for the placebo and bupropion groups. 
For the week-10 comparison, we expect that the quit rates in the placebo and bupropion arms 
would approximate those reported in bupropion trials in the general population of smokers (i.e., 
placebo = 21.2%; bupropion = 35.9%, OR = 2.1; ref. 44). A sample of 360 provides 88% power 
to detect a significant between-group effect. The OR for bupropion treatment is similar at 24 
weeks, based on Jorenby et al. (168) and our own data, and results from 10 and 24 weeks are 
highly correlated (rho>0.7). Thus, we have 80% power to detect a significant difference between 
treatment arms. 
 
Safety analyses (H2) will examine maternal safety across the 10-week treatment and 24-week 
follow-up periods and fetal and birth outcomes. Key maternal and fetal outcomes to be 
compared across treatment groups include rates of moderate-to-severe side AEs of bupropion 
(from the AE checklist).  Key birth outcomes will include Apgar scores, birth weight, duration of 
pregnancy, rate of obstetrical complications, and need for NICU admission.  These analyses will 
involve a test of equivalence because we cannot use standard statistical tests to conclude that a 
non-significant comparison shows that the drug is safe (i.e., “the absence of evidence is not 
evidence of its absence”). In our past study with bupropion, 45% of bupropion-treated 
participants reported no moderate-to-severe AEs, vs. 47% of participants on placebo, a 2% 
difference. With the present sample size, we will have 82% power to detect similar equivalence 
between treatment arms on the frequency of moderate-to-severe AEs over the course of the 
trial, given that AEs are not significantly different between treatment arms, using an equivalence 
window of 0.30 to 0.60. Likewise, Oncken et al. (47) reported 38% AEs for the placebo group 


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and 25% in the nicotine group.  An equivalence test with placebo and bupropion groups both at 
30% and an equivalence window for bupropion of +/-15% provides 81% power. 
 
For H3, we have very high power.  Oncken et al. (47) found a difference in birth weight between 
groups of 337 g, which yields an effect size > d=0.5.  The power to detect a difference of that 
magnitude will exceed 99%, and we have 80% power to detect a difference as small as 180 
grams.  We also have >89% power to detect differences in secondary analyses of the frequency 
of low birth weight and preterm delivery. 
7.1.2. Aim 2:  
Analyses here will assess changes in craving and depression symptom scores as mediators of 
bupropion treatment effects at weeks 10 of treatment and 24 weeks post-TQD. These measures 
are continuous difference scores. Our sample of 360 is well above the minimum sample of 200 
recommended for such analyses (169-170). The mediation hypotheses will examine the 
proportion of variance in treatment effect explained (171-172), and we will test each mediation 
hypothesis with a z-score generated using the delta method. Our sample of 360 gives us 80% 
power to observe small effects in a 1-sample test (δ = 0.16) when testing at α = 0.05. There are 
2 proposed mediating pathways (depression and craving) between treatment and outcome, so 
our type-1 error will be corrected to 0.025. A sample of 360 gives us 80% power to detect small-
to-medium effects (δ=0.35 SD) for changes in the proposed mediators, which we have seen in 
previous trials (15, 52). 
7.2. 
Statistical Analyses 
Dr. Kevin Lynch will oversee analyses, which will be conducted using Stata, SAS, or R-
Language software. Preliminary analyses will assess sample characteristics (e.g., dependence, 
race) by treatment using t-test or contingency table methods. These variables will also be 
examined for their relationship to completion of outcome assessments. Variables related to 
treatment arm or completion of follow ups will be included as covariates in analyses of study 
aims. Compliance measures will be evaluated across treatment arms, and controlled for in 
primary analyses. We will examine the correlation between self-report and pill count data and 
week-5 bupropion plasma levels. We will use intent-to-treat as the primary method to evaluate 
study aims. 
7.2.1. Missing Data: 
We will examine whether the rate of missing data, primarily our smoking cessation outcome 
data, is related to a range of potential variables, including treatment arm allocation, and 
demographic and smoking-related variables. Standard bivariate statistical methods will be used 
to identify correlates of missing data. Variables associated with the rate of missing data (p < 
0.05) will be included as covariates in the analyses of aims. Items missing at random from 
assessments will be imputed prior to calculating final scores using conditional means, estimated 
with an iterated version of Buck’s method (173). We will aim to avoid dropout and missed 
sessions by keeping participants connected to the trial and motivated to complete measures. In 
our clinical trials, close monitoring of participants and the use of incentives to offset travel costs 
have resulted in adherence and retention rates >80% (52). Primary analyses will assume that all 
participants for whom smoking outcome data are unavailable are smokers (intent-to-treat), 
which is conventional in smoking cessation research.  Because this assumption can attenuate 
the differences between study groups in quit rates, we will also conduct a “completers-only” 
analysis, as done previously (174). 
 


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7.2.2. Specific Aim 1: To compare the efficacy of bupropion with placebo for smoking 
cessation in pregnant smokers.   
For H1, we will test for treatment group differences in a binary abstinence outcome that is a 
repeated measure using a generalized estimating equations (GEE) model with a logit link.  Quit 
rates at the end of week 10 of treatment and 24 weeks post-TQD will represent our primary 
outcome variables.  Medication group (bupropion vs. placebo) and time point (end of week 10 of 
treatment and 24 weeks post-TQD) will be treated as categorical predictor variables, and the 
model will predict separate effects of treatment on abstinence at each time point (an 
interaction).  Our initial analyses will be stratified by site, and we will carefully examine the 
models for differences by site, testing for an overall interaction.  We will use baseline depression 
(PHQ-9 score of 10) to stratify the randomization.  The model may include a small number of 
covariates added to control error or adjust for confounding [e.g., age, history of pre-term 
delivery, baseline gestational age, daily smoking rate].  Any variables found to be associated 
with both outcome and treatment assignment will be entered as covariates.  In the absence of 
an overall interaction (by site), we will pool the study population and account for site in the 
model as a binary predictor.  To evaluate the effectiveness of randomization, we will compare 
summary statistics for participant characteristics in the two study arms.  If there is an imbalance 
in participant characteristics, statistical adjustment will be used to ensure that the initial results 
were not biased by it.   
 
Because many participants will fail to become completely abstinent, but may show a reduction 
in smoking, we will examine cigarette consumption as a secondary outcome.  The analysis will 
be similar to the primary analysis, except that we examine the effect of treatment arm on daily 
cigarette counts using a GEE model with a negative-binomial link.  Likewise, time to (recurrent) 
event models will be fitted using Cox regression, stratified by event sequence, as in Schnoll et 
al. (52), to assess lapse and recovery events over 24 weeks. 
 
H2: We will compare treatment arms for equivalence of the frequency of moderate-to-severe 
AEs (individual and total). The hypothesis test for equivalence is a test of whether the OR is out 
of the prescribed range for the difference between the treatment arms.  Using logistic 
regression, we will conduct two one-sided tests against predefined upper and lower equivalence 
boundaries on percent reporting only mild AEs. The test-statistic will be the z-score 
corresponding to the log of the OR.  This provides a more valid test of the potential safety of 
bupropion for pregnant smokers than a simple comparison of mean responses on a measure of 
AEs. 
 
H3: Mean birth weight will be compared for treatment groups using a two-sample t-test, in the 
context of multiple linear regression.  The regression format allows us to add covariates to 
adjust for imbalances in participant characteristics between treatment arms. Treatment will be 
entered as a binary indicator. In a secondary analysis, we will also compare the percentage of 
participants in each group that delivers an infant of LBW (1500-2500 g) or preterm delivery. 
These secondary hypotheses will be tested using the z-score corresponding to the OR that will 
be estimated using logistic regression.   
 
7.2.3. Specific Aim 2: Assess changes in depression symptoms and craving as mediators 
of bupropion’s effect on quit rates.  
We will use a regression-based path model approach to examine mediation of treatment effects 
based on MacKinnon et al. (175). All variables will be standardized for the analyses. The two 
suspected mediators will be entered as standardized pre-post differences, continuously 
distributed and treated as normal in linear regression. The effects of treatment arm on 


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mediators, and of mediators on outcome, will be assessed using linear regression and 
standardized variables. We will focus on changes in mediators from baseline to week 3, since 
abstinence-induced withdrawal effects typically peak within the first 3 weeks of cessation (174), 
but we can examine delayed changes to weeks 5, 7, and 10 as well. Assuming that treatment 
predicts our mediators, we will then assemble the path model using standard structural equation 
modeling approaches. The path model partitions the effect of treatment on outcome into direct 
(and unexplained) effects vs. mediated effects. We will then test the overall mediation 
hypothesis using the proportion of treatment effect explained (171-172), and the strength of 
each mediating pathway. To do this, we will estimate the model for standardized treatment 
predicting abstinence without mediators to estimate the direct effect of treatment in the 
unadjusted model (
†ˆβ ). We will then test whether treatment predicts each of the suspected 
mediators and, in turn, test whether mediators predict abstinence in an adjusted treatment 
model and estimate the effect of treatment in the mediator adjusted model
*ˆβ . Finally, we will 
calculate the proportion of treatment effect explained, which is calculated as(
)
†
*
ˆ
ˆ
β
β
; the 
standard error for this quantity is calculated using the delta method, and the mediation 
hypothesis will be tested using a z-test. Individual pathways will be tested using products of the 
coefficients along each path using a delta-method based z-test. 
 
7.2.4. Specific Aim 3: To explore genetic, metabolic, and social/behavioral moderators of 
the efficacy of bupropion on cigarette abstinence and safety.  
These variables may either be continuous, or categorical, and we will address the aim by testing 
for moderation using the analytical models in Aim 1, testing for interactions with treatment.  We 
will explore whether the risk of AEs and the efficacy of bupropion treatment (vs. placebo) is 
moderated by: 1) the rate of nicotine metabolism (i.e., NMR) and variation in CYP2A6; 2) the 
rate of bupropion metabolism (i.e., variation in CYP2B6 and plasma concentrations of bupropion 
and hydroxybupropion); and 3) variation in social/behavioral variables, including weight 
concerns, body image, adverse childhood experiences, and the presence of other smokers in 
the home.  Because this is exploratory, we will test at α = 0.05, using the z-score for the 
interaction term for binary or continuous predictors, or the Wald χ2 for categorical predictors. 
7.3. 
Participant Population for Analysis 
Data from protocol-compliant participants will be used for analysis. 
8. Safety and Adverse Events 
8.1. 
Definitions 
Adverse Event - Maternal 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  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 
 


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Serious Adverse Event - Maternal 
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 
• 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 participant wellbeing, 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 inpatient 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 should be regarded as non-
serious adverse events.  
 
Adverse Event – Neonate 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during gestation or at birth. Intercurrent illnesses or injuries should be regarded as 
adverse events.  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 
• results in prolonged hospitalization in the NICU due to neonatal abstinence syndrome 
(expected for babies exposed to methadone or buprenorphine) or premature birth 
(expected for babies whose mothers’ smoke)  
• conditions associated with premature birth, such as patent ductus arteriosus 
 
Serious Adverse Event – Neonate 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
develops or worsens in severity during gestation or at birth that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay in the NICU (except for neonatal abstinence syndrome) 
• results in persistent or significant disability or incapacity 
• results in a congenital anomaly or birth defect 
• results in any unexpected condition not explained by gestational history 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the participant wellbeing, 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 inpatient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered serious. 
 


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Adverse Event Reporting Period 
The study period during which adverse events must be reported will be defined as the period 
from the initiation of any study procedures to the end of the last assessment.  
 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study.  A pre-existing condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
At screening, any clinically significant abnormality or disorder should be recorded as a pre-
existing condition.  At the end of the study, any new clinically significant findings/abnormalities 
or disorder that meets 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 investigator until the events are resolved, 
the participant is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each participant to report any subsequent 
event(s) that the participant, or the participant’s personal physician, believes might reasonably 
be related to participation in this study.  The investigator should notify the IRB of any adverse 
event occurring at any time after a participant has discontinued or terminated study participation 
that may reasonably be related to this study.  The IRB will also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a participant that has participated in this study.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should 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 should 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. Thus, hospitalization for normal childbirth is not considered an 
adverse event. 
8.2. 
Recording of Adverse Events 
At each contact with the participant, an investigator or staff member must seek information on 
adverse events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related signs, 


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symptoms, and abnormal diagnostic procedures results should be recorded in the source 
document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should 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 should be recorded and reported immediately. 
8.3. 
Reporting of Serious Adverse Events and Unanticipated Problems 
8.3.1. IRB Notification by Investigator 
A Serious Adverse Event (SAE) must be reported to the IRB within 72 hours of the event. The 
investigator will keep a copy of this SAE form in the study binder.  
 
At the time of the initial report, the following information will be provided: 
Study identifier 
 
Whether study participation was 
discontinued 
Study Center 
Participant number 
  The reason why the event is classified 
as serious 
A description of the event 
Date of onset 
 
Investigator assessment of the 
association between the event and 
study participation 
 
 
Current status 
Significant new information on ongoing serious adverse events should be provided promptly to 
the IRB. 
8.4   Unblinding Procedures 
In the event that participants are prematurely discontinued, it will be necessary to avoid 
breaking the blind whenever possible, in order to protect the integrity of the study. If an 
emergency necessitates that the blind be broken, only the pharmacist will have access to the 
unblinding codes and will be given the names of the staff with authority to request that the blind 
be broken. If the IDS or hospital pharmacy is contacted by other persons in requesting the study 
blind be broken for a participant, and the study physician is not reachable, the pharmacist will 
act according to his/her best judgment in deciding whether or not to break the study blind for 
that participant. The hospital pharmacist can be reached 24 hours a day by beeper to rapidly 
access participant unblinding codes. 
The pharmacy emergency beeper number is: 215-555-1212. 
8.5   Medical Monitoring 
It is the responsibility of the principal investigator at each site to oversee the safety of the study 
at that site. This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above.  Medical monitoring will involve regular staff meetings to 
assess the number and type of adverse events; these meetings will be held separately at the 
different sites.  There will be a single Data and Safety Monitoring Board for the study, which will 


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meet twice annually to oversee safety issues for the whole study (see Section 10 Auditing, 
Monitoring and Inspecting). 
8.6   Protection of Participants 
Complementing the safety measures noted above, additional procedures will be followed to 
protect the safety of the research participants. Potential participants will be screened for medical 
illnesses that would preclude the use of bupropion. Participants selected for the study will be 
evaluated regularly while receiving study drug treatments, both by study staff at periodic visits 
(as described in Table 2) and by obstetrics staff for their routine prenatal monitoring.  AEs will 
be monitored regularly in-person or by telephone (see Table 2) and a study physician will be 
available at all times to evaluate and treat adverse effects of the medication. The participants’ 
weight and blood pressure will be monitored during their standard prenatal visits and pulse rate 
will be measured at all in-person visits (see Table 2).  AEs that reflect significant risk to the 
participant or fetus will result in discontinuation of the study medication, a decision that will be 
made by the site principal investigator together with the study obstetrician at that site.  
Venipuncture will be carried out with good aseptic technique by an experienced phlebotomist, 
nurse, or physician. Venipuncture sites will be monitored carefully for signs of infection. 
Participants will be given a 24-hour emergency number that they can call if necessary. The 
physician or nurse will clinically follow all participants who are discontinued due to a serious AE 
until the AE resolves and becomes completely stable, unless a referral to another physician 
(i.e., a specialist) is clinically indicated or requested by the participant.  
9. Data Handling and Record Keeping 
9.1. 
Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed authorization informing the participant of the following:  
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the participant’s revocation 
of authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
will be made to obtain permission to collect at least vital status (i.e. that the participant is alive) 
at the end of their scheduled study period. 
 
Records, filed in the IRB office, verify that all research project personnel have completed 
training in the protection of human research participants in accordance with the guidelines of the 
U.S. Department of Health and Human Services (DHHS) and the Office for Human Research 
Protection (OHRP).  The study staff (PI, Clinical research coordinator, etc.) will keep all study 
medical records (including any codes to de-identified data) under lock and key in a secure 
location, as required by law. Only the date and time of the research visit will be placed in the 
client’s existing electronic medical record. All electronic data and files (e.g., database, 
spreadsheet, etc.) containing identifiable participant information shall be password protected.  
Any computer hosting such files shall have a BIOS password to prevent access by un-
authorized users.  If participant data are to be exchanged with others, the data will be coded. If 
identification is necessary, then the data will be encrypted while en route to the recipient with 


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strong encryption levels (≥ 128 bits for symmetric encryption (DES) and ≥ 1024 bits for 
asymmetric encryption (RSA). All information collected via the social media landing page will be 
stored securely our Data Management Unit (DMU). 
 
All data and blood specimens will be stored without direct identifiable information, but will be 
identifiable via a linking code. The secured research records are labeled with code numbers 
only (names and other identifying information are kept separate from research records). Access 
to hard copy data is only given to staff members working on the study. Only staff members 
designated to handle or analyze study samples will have access to the samples and their 
storage. Coded blood samples are stored in clinic-specific refrigerators and freezers, which are 
located in secure rooms. As per routine in the CSA, all electronic files (e.g., database, 
spreadsheet) will be password protected. Any computer hosting such files will have a BIOS 
password to prevent access by un-authorized users.  
 
Text messaging will be done in conjunction with Sense Health, a contractor with substantial 
experience in the use of text messaging in health applications.  The Sense Health web service 
was built on top of the Amazon Web Services (AWS) cloud infrastructure, a highly secure and 
scalable service, that was designed in alignment with HIPAA regulations, standards, and best 
practices. The underlying code for the web service is version-controlled and securely backed-up 
on the GitHub.com. A variety of security measures have been implemented to protect PHI: 
 
Administrative Safeguards: All Sense Health staff members are trained to understand 
the core requirements of HIPAA, and only authorized staff members have access to 
data stores that contain any PHI. Furthermore, any database containing PHI data is de-
identified, so that patient information is protected even if that database is compromised. 
 
Physical Safeguards: All of the Sense Health data and code are stored on secure 
cloud infrastructures such as AWS and GitHub, which were designed to comply with 
HIPAA regulations and best-practices. 
 
Technical Safeguards: 
Access control: Only authorized staff members can access the Sense Health servers on 
AWS and the code repository on GitHub. This access is only possible via SSH tunneling. 
Therefore, only authorized staff members on authorized machines can access the  
servers and code. 
 
Transmission security: All communication between servers and the outside world is 
encrypted during transmission using Class 3 SSL certificates on port 443 only. 
 
Data encryption: All PHI data are encrypted and stored on a MySQL AWS RDS database 
that is inaccessible to the outside world. This information is encrypted before it is stored 
on the database, using standard AES encryption protocols. Therefore, all patient data are 
de-identified before they are stored at rest. 
 
Data Backups: The Sense Health databases, code, and server images are backed up 
both daily and hourly and stored on separate AWS availability zones, so that data are 
never lost and can be easily recovered when needed. 
 
Data Disposal: All PHI can be permanently disposed of when no longer needed by 
removing those data from all active and backed-up AWS RDS databases. 
 


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Blood will be collected for DNA analysis. The information derived from analysis of the 
participants’ DNA will not be provided to the participants, since at the present time the existing 
preliminary genetic data for predicting response to bupropion do not provide a basis for genetic 
counseling. Should that situation change over the course of the study, procedures will be 
developed in conjunction with the UPenn and City of Philadelphia IRBs, to provide participants 
with relevant information on genotype and to counsel them in relation to that information. While 
the study is open, DNA samples will be coded with a number that provides an indirect link to the 
participant’s identity (samples will be accessible only by the researchers and staff involved with 
this study). Upon completion of the study, the sample will be kept in storage indefinitely. 
However, the sample will forever be separated from all identifiers. These de-identified samples 
may be shared with other researchers and used in other projects. The lab procedures for 
storage include a passcode-protected locked room, and secure storage freezers.  All samples 
will be retained securely as per lab protocols.  
 
Data used to process subject payments with the Greenphire ClinCard program is entered 
electronically using secure web-based interfaces. Greenphire clinicard is HIPAA compliant. 
Please see document titled, “ClinCard Data Security and Privacy Statement,” located in the  
appendix. The Greenphire system requires completing a W9 for each subject, and entering 
subject’s name, address and social security number.  
 
9.2. 
Source Documents 
Source data consists of all information, original records, observations, or other activities during 
participation in the study.  Source data are contained in source documents.  Examples of these 
original documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, evaluation checklists, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, participant files, and records kept 
at the laboratories. 
9.3. 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in blue or black ink.  If any entry error has been made, to correct such an error, 
draw a single straight line through the incorrect entry and enter the correct data above it.  All 
such changes must be initialed and dated. 
9.4. 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 3 years after 
the closure of the study with the IRB.  
 
9.5.     Blood samples storage and retention. 
Blood for both the UPenn and Jefferson sites will be stored in a coded manner in a designated   
-80 degree freezer at UPenn and shipped to the laboratory of Dr. Rachel Tyndale at the 
University of Toronto, on dry ice approximately every four months or as necessary for the 
duration of the study. Samples will be shipped following the University of Pennsylvania’s 


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guidelines for shipping international biological samples. Samples will be coded and protected 
health information will not be included.  DNA extraction and genotyping will be carried out in Dr. 
Rachel Tyndale’s laboratory. The nicotine metabolite ratio (NMR), a genetically informed 
biomarker based on the measurement of two long-lasting nicotine metabolites (cotinine and 3-
hydroxycotinine), will also be measured.  Finally, bupropion and hydroxybupropion plasma 
concentrations will be measured using blood obtained at the week-5 visit.   
10. Study Monitoring, Auditing, and Inspecting 
10.1. Study Data and Safety Monitoring Plan 
This study will be monitored according to the attached Data and Safety Monitoring Plan (DSMP) 
version 1, dated 7/6/2016 (see Appendix). The DSMP includes 100% source data verification to 
be performed for each subject, at each site, to ensure that all of the essential aspects of the 
Sponsor’s oversight of the research at all sites are addressed.  The Principal Investigator will 
identify an appropriately trained staff member and allocate adequate time and supervision for 
such monitoring activities to occur. The Investigator will also ensure that the monitor  is given 
access to all of the study-related documents and,  has adequate space to conduct the 
monitoring visit.   
SAFETY MONITORING AND REPORTING PROTOCOL 
Adverse Event Determination and Reporting Procedures.  For this study, we will use 
established Penn procedures and infrastructure for data and safety monitoring and a protocol-
specific Data and Safety Monitoring Board (DSMB). The specific elements of our plan is as 
follows: 1) all project staff will complete certification in the protection of research participants; 2) 
the protocol will be submitted for review to the IRB and all procedures and policies outlined by 
the IRB will be followed for this study; and 3) a DSMB will be established to review the progress 
of accrual and the safety of participants. We will supply the designated IRB with ongoing 
progress reports for the study and a formal review of the study will be conducted annually or 
more frequently as designated by the IRB. The Penn IRB will act as the IRB of record for both 
sites per the IRB Authorization Agreement signed by both sites. The City of Philadelphia IRB 
will receive an annual report and be informed of all SAEs and reportable events. The IRB may 
suspend, terminate or restrict the study as appropriate. Each participating investigator must 
complete certification in the protection of research participants. Finally, Dr. Kranzler (at Penn) 
and Dr. Hand (MATER/Jefferson) will manage the flow of documents to external agencies to 
facilitate ongoing and timely review. The IRB will audit the study as needed and will review all 
data on a regular basis at least every 12 months. All serious adverse events (SAEs) will be 
reviewed on a real-time basis first by the study physicians. An existing protocol for adverse 
event monitoring and adverse event reporting will be used (see below). The DSMB will consist 
of four individuals who are not involved in the study: a statistician (Richard Feinn, Ph.D., 
Assistant Professor of Medical Science at Quinnipiac University), an obstetrician (Samuel 
Parry, M.D., Associate Professor of Obstetrics and Gynecology at Penn),  a clinical trialist 
(David Oslin, M.D., Professor of Psychiatry at Penn) and a women’s behavioral wellness 
specialist (Neill Epperson, MD, Professor of Psychiatry and Ob/Gyn at Penn). The DSMB will 
establish guidelines for adverse event reporting.  The DSMB will meet annually, with additional 
meetings, as may be required.  Prior to meetings, all members of the DSMB will receive a 
report describing study progress, including enrollment, treatment completion or early 
termination, and a summary of all adverse events.  A formal data and safety monitoring plan, 
detailing the DSMB’s activities, will be submitted to the IRB for review and approval prior to 
study initiation and periodic reports will be included with annual IRB reviews.  
 


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PARTICIPANT SAFETY MONITORING PROTOCOL 
 
Monitoring Participant Safety. For this trial, we will use a method to track, manage, and report 
adverse events that was used in completed studies (14, 43, 52) and is being used in an ongoing 
(U01 DA020830) pharmacotherapy trial. First, in terms of personnel, each clinical site will 
include a study physician, a study psychologist, and a research nurse/qualified medical staff 
person to handle comprehensive eligibility screening, monitoring of participant reactions and 
adverse events, and the management of any adverse events. The initial eligibility screening 
procedures will involve careful assessment of participants’ medical history to ensure that 
individuals with pre-existing conditions that can increase adverse event risk are excluded. 
Second, we will use a two-tiered system to assess potential adverse events. Site staff will 
complete a baseline adverse event checklist (week 0). At weeks 1, 3, 5, 7, and 10, staff 
members will conduct an open-ended evaluation of any potential adverse event and complete 
the established checklist of adverse events. Lastly, as done in our previous clinical trials, 
participants will be provided with contact information (a wallet-size card) so that, if a serious 
adverse event occurs, they have methods to contact study staff at their respective clinical site 
24 hours a day.  Because participants may try to communicate regarding adverse events 
through the daily text messaging service, which will not be monitored for this purpose, we will 
provide contact information via an auto-message informing the participant of how to reach study 
staff in an emergency. 
 
For all adverse events, the site nurse practitioner, in consultation with the site PI and the 
obstetrician at each site (as needed), will determine a course of action (i.e., continuation and 
monitoring, dose reduction, participant withdrawal). All adverse events that are considered 
Serious Adverse Events (see below) will be reported to site PIs and IRBs at all clinical sites, as 
well as to the FDA and NIH (see below for protocol for adverse event reporting). Site PIs and 
study physicians will determine whether a serious adverse event requires additional care. Such 
events may be referred to the outpatient department at the clinical site or to the emergency 
department of the clinical site (all sites have access to 24-hour emergency services, including 
extensive inpatient and outpatient services for psychiatric conditions). 
 
MEASURES FOR PARTICIPANT SAFETY. 
 
 
Medication Adverse Events Checklist. An adverse events checklist will assess the 
frequency and severity of common adverse events associated with bupropion (rated as: none, 
mild, moderate, or severe). This measure will be conducted at weeks 1, 3, 5, 7, and 10. This 
assessment is meant to monitor participant safety and reduce or stop treatment if need be. But, 
adverse events will be considered an outcome and a covariate in the analysis, as the overall 
frequency and/or as the presence (ever) of specific common adverse events. Our adverse 
events measure includes items that have been reported from bupropion use.  In addition, we will 
monitor the prenatal care record to identify adverse obstetrical events, which will be recorded and 
reviewed regularly by the study team at each site.  The data will be fully abstracted at the time of 
delivery for use in data analysis, which will provide a second opportunity to review obstetrical 
adverse events that may have occurred during the pregnancy. 
 
 
Open-ended Questions. In addition, open-ended questions concerning adverse events 
are assessed at these weeks. Staff will probe for physical and psychiatric adverse events. This 
method is included to supplement standard adverse event measures so non expected adverse 
events will be captured.  Events will be classified as none, mild, moderate, or severe. 
 
PARTICIPANT ADVERSE EVENT REPORTING PROCEDURES. 


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For any reported adverse event: While with the participant, study personnel will listen, identify, 
and document the adverse event, which may not be related to medication and may not be a 
Serious Adverse Event. The protocol for recording adverse events and reporting the event is 
listed below: 
 
• 
The symptom MUST be coded by its severity and responded to according to the 
following protocol (please see tables below for symptom coding). 
• 
Severity Definitions: None = no concerns, Mild = Adverse event does not interfere with 
usual daily activities; Moderate = Adverse event interferes with some activities; Severe = 
No normal activities are possible. 
 
 
Code 1 
Response 
Code 2 
Response 
Code 3 
Response 
Code 4 
Response 
Adverse Event Checklist: If adverse event severity is not listed, no report is required unless the 
participant requests that the study physician be consulted. 
1. Irritability 
 
Moderate 
Severe 
 
2. Irregular heartbeat 
 
Mild 
Moderate 
Severe 
 
3. Depressed mood 
Mild 
Moderate 
Severe 
 
4. Increased heart rate or   
    palpitations 
 
Mild 
Moderate 
Severe 
 
5. Suicidal thoughts, ideation 
 
 
Any Reporting 
 
5b. Suicide Attempt 
 
 
 
Any Reporting 
6. Nausea (without vomiting) 
 
Moderate 
Severe 
 
7. Sleep problems 
 
Moderate 
Severe 
 
8. Constipation 
 
Moderate 
Severe 
 
9. Vomiting 
 
Mild 
Moderate 
Severe 
 
 
10. Dry Mouth 
 
Moderate 
Severe 
 
11. Gas 
 
Moderate 
Severe 
 
12. Anxiety 
 
Moderate 
Severe 
 
13. Skin swelling or rash 
 
Moderate 
Severe 
 
14. Indigestion 
 
Moderate 
Severe 
 
15. Agitation 
 
Mild 
Moderate 
Severe 
 
16. Insomnia 
 
Moderate 
Severe 
 
17. Headache 
 
Moderate 
Severe 
 
18. Abnormal dreams 
 
Moderate 
Severe 
 
19. Disturbance in   
      Attention 
 
Moderate 
Severe 
 
20. Diarrhea 
 
Severe 
 
 
21. Abdominal Pain 
Mild 
Moderate 
Severe 
 
22. Flatulence  
 
Moderate 
Severe 
 
23. Dizziness 
 
Moderate 
Severe 
 
24. Fatigue 
 
Moderate 
Severe 
 
25. Feeling of Weakness 
 
Moderate 
Severe 
 
26. Skin Redness 
 
Moderate 
Severe 
 
27. Hostility 
 
Mild 
Moderate 
Severe 
 
28. Chest pain 
 
Mild 
Moderate 
Severe 
 


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29. Weakness of one or both 
sides of the body 
 
Mild 
Moderate 
Severe 
 
30. Blurred vision 
 
Mild 
Moderate 
Severe 
 
31. Sweating 
 
 
Severe 
 
32. Strange taste 
 
 
Severe 
 
33. Ringing in ears 
 
Mild 
Moderate 
Severe 
 
34. Tremors 
 
Mild 
Moderate 
Severe 
 
35. Seizure 
 
 
 
Any Reporting 
36. Fainting (loss of 
consciousness) 
 
 
Any Reporting 
 
37. Confusion 
 
Moderate 
Severe 
 
38. Muscle aches 
 
Moderate 
Severe 
 
39. Shortness of Breath 
 
Mild 
Moderate 
Severe 
 
 
Open-ended Responses (this is not an exhaustive list) 
1. Allergic reaction  
Mild 
Moderate 
Severe 
 
2. Appetite loss 
Moderate 
Severe 
 
 
3. Asthma 
 
Moderate 
Severe 
 
4. Blood pressure increase 
 
Moderate 
Severe 
 
5. Cancer 
 
 
 
Any Reporting 
6. Change in taste perception 
 
Moderate 
Severe 
 
7. Chest pain 
 
Mild 
Moderate 
Severe 
 
8. Trouble concentrating 
 
Moderate 
Severe 
 
9. Death 
 
 
 
Any Reporting 
10. Emergency Room Visit 
 
 
 
Any Reporting 
11. Heart Attack/MI 
 
 
 
Any Reporting 
12. Heartburn 
 
Moderate 
Severe 
 
13. Hospitalization 
 
 
 
Any Reporting 
14. Itching 
 
Moderate 
Severe 
 
15. Lightheadedness 
Mild 
Moderate 
Severe 
 
 
16. Nose Bleed 
 
Moderate 
Severe 
 
 
17. Neurological event  
      Stroke/TIA, etc 
 
 
 
Any Reporting 
18. Psychiatric event  
      (not related to suicide) 
 
Mild 
Moderate 
Severe 
 
19. Racing thoughts 
 
Moderate 
Severe 
 
20. Runny nose 
 
Moderate 
Severe 
 
21. Sore throat 
 
Moderate 
Severe 
 
 
Code 1 Events 
• 
Documented either on Adverse Event Checklist or on Open-Ended AE Form 
 
• 
If reported at a scheduled visit, email sent to Site PI, Site Study Physician, and Site 
Coordinator for review within 72 hours 
 
Email should be based on the following template: 


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Today, an adverse event assessment with participant XXXXXXX was completed.  This 
session was conducted at week X, X weeks after study medication was initiated. During 
the assessment the participant reported [mild/moderate/severe] _______ (Code X). 
 
This adverse event was (or was not) reported at a previous assessment.  
The participant is currently/not currently smoking and is/is not on protocol with taking study 
medication.   
 
o Internally reviewed by the PI and/or Study Physician. 
o Response printed out and filed in the participant chart.   
o The participant will continue in the trial unless they decline to do so. Medication 
can be continued. 
 
• 
The physician can evaluate the information presented in the email along with any further 
information received from contact with the participant and, based on clinical judgment, 
change the code that the event received (either increasing in severity or decreasing in 
severity).  
 
• 
If reported to site staff between scheduled sessions, email sent to PI, Study Physician, 
and Study Coordinator for review within 48 hours as above. 
 
Code 2 Events  
• 
Documented either on Adverse Event Checklist or on Open-Ended SE Form 
 
• 
If reported at a scheduled visit, email sent to Site PI, Site Study Physician, and Site 
Coordinator for review within 24 hours (obstetrician to be consulted, as needed). 
 
Email should be based on the following template: 
 
Today, an adverse events assessment with participant XXXXXXX was completed.  This 
session was conducted at week X, X weeks after study medication was initiated. During 
the assessment the participant reported [mild/moderate/severe] _______ (Code X). 
 
This adverse event was (or was not) reported at a previous assessment.  
 
The participant is currently/not currently smoking and is/is not on protocol with taking study 
medication.  Please let me know whether - after your review - the SEC codes should be 
modified &/or if further action should be taken. 
 
o Internally reviewed by the site PI and/or Study Physician. 
o Response printed out and filed in the participant’s research chart.   
o Participant may continue medication unless she thinks that the medication is 
making her symptoms worse or wants to stop (or the Study Physician tells her to 
stop).   
o Dose adjustments can also be considered. 
o The Study Physician will follow-up with the participant as deemed appropriate. 
 
• 
The study physician/PI can evaluate the information presented in the email along with 
any further information received from contact with the participant and, based on clinical 


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judgment, change the code that the event received (either increasing in severity or 
decreasing in severity). The SEC data may be changed accordingly. 
 
If reported to site staff between scheduled sessions, email sent to PI, Study 
Physician, and Study Coordinator for review within 24 hours as above 
 
Code 3 Events 
• 
Regardless of when Code 3 events are reported, they will be considered urgent and 
follow-up will be immediate.   
 
• 
Staff can advise participants to contact their physician immediately or call 911. 
 
• 
If the participant is currently taking study medication, she will be instructed to discontinue 
the medication pending additional consultation with her doctor or a Study Physician. 
 
• 
If reported during a visit, the site physician and/or PI will be notified immediately 
by phone or in-person to address the report immediately (see template below for 
call). The physician may be contacted via pager so that the situation can be resolved 
quickly.  The study doctor will evaluate the problem and, if needed, contact the maternal-
fetal medicine attending (during regular hours) or the maternal-fetal medicine fellow on- 
call (during off hours). 
 
• 
An email is also sent for documentation as follows to the study physician, PI and 
coordinator. 
 
Email (or conversation) should be based on the following template: 
 
Today, an adverse events assessment with participant XXXXXXX was completed.  This 
session was conducted at week X, X weeks after study medication was initiated. During 
the assessment the participant reported [mild/moderate/severe] _______ (Code X). 
 
This adverse event was (or was not) reported at a previous assessment.  
 
The participant is currently/not currently smoking and is/is not on protocol with taking study 
medication.  Please let me know if - after your review - the SEC codes should be modified 
&/or if further action should be taken. 
 
o Study Physician will oversee recommendations and follow-up with the participant 
until the event is resolved or the participant is stable. 
o Study Physician will report to the PI. 
o Response printed out (or conversation documented) and filed in the participant’s 
research chart.   
 
• 
The physician can evaluate the information presented in the email/telephone call or in-
person assessment along with any further information received from contact with the 
participant and, based on clinical judgment, change the code that the event received 
(either increasing in severity or decreasing in severity). The SEC data may be changed 
accordingly. 
 
• 
These events may be considered Serious Adverse Events, requiring additional reporting 


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(see below). 
 
• 
If reported to site staff between scheduled sessions, email or phone call to PI, Study 
Physician, and Study Coordinator for review immediately, following the procedures 
above. 
 
Code 4 Events 
• 
Code 4 events may not be associated with bupropion use, but will be recorded and 
immediately reported to the entire Research Team. 
 
• 
Code 4 events are considered urgent and follow up will be immediate.   
 
• 
Code 4 events are serious, unanticipated health events that happened after 
enrollment/since the last call (i.e. requiring MD, ER or hospital care). These include 
death, MI, stroke, transient ischemic attack, cancer diagnosis, pneumonia or 
COPD/Asthma/CHF exacerbation. Hospital visits for non-life threatening events or 
anticipated procedures may not require study withdrawal. 
 
• 
If applicable, staff can advise participant to contact her physician immediately or call 
911. 
 
• 
If the participant is currently taking study medication, she will be instructed to discontinue 
the medication pending additional consultation with their doctor or the Study Physician. 
 
• 
If reported during a visit, the site physician and/or PI will be notified immediately 
by phone or in-person to address the report immediately (see template below for 
call). The physician may be contacted via pager so that the situation can be resolved 
quickly.  The study doctor will evaluate the problem and, if needed, contact the maternal-
fetal medicine attending (during regular hours) or the maternal-fetal medicine fellow on- 
call (during off hours). 
 
Email (or conversation) should be based on the following template: 
 
Today, an adverse events assessment with participant XXXXXXX was completed.  This 
session was conducted at week X, X weeks after study medication was initiated. During 
the assessment the participant reported [mild/moderate/severe] _______ (Code X). 
 
This adverse event was (or was not) reported at a previous assessment.  
 
The participant is currently/not currently smoking and is/is not on protocol with taking study 
medication.  Please let me know if - after your review - the SEC codes should be modified 
&/or if further action should be taken. 
o Study Physician will oversee recommendations and follow-up with the participant 
until the event is resolved or the participant is stable. 
o Study Physician will report to PI. 
o Response printed out (or conversation documented) and filed in the participant 
chart.   
 
• 
The physician can evaluate the information presented in the email/telephone call or in-
person assessment along with any further information received from contact with the 


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participant and, based on clinical judgment, change the code that the event received 
(either increasing in severity or decreasing in severity). The SEC data may be changed. 
• 
These events may be considered Serious Adverse Events, requiring additional reporting 
(see below). 
• 
If reported to site staff in between scheduled sessions, email or phone call to PI, 
Study Physician, and Study Coordinator for review immediately, following the 
procedures above. 
 
Additional Reporting Requirements (IRB, NIH, FDA) 
 
Reporting 
• 
The study site coordinators are responsible for reporting adverse events that are 
considered serious adverse events to their IRB 
• 
Generally only Code 3 or Code 4 events would be classified as Serious Adverse Events, 
reportable to IRBs, NIH, and FDA 
• 
Note that the a Serious Adverse Event may not be related to the participant’s treatment. 
• 
Any death is a Serious Adverse Event, and shall be reported immediately whether it is  
related to study participation or not. 
 
Reporting of Serious Adverse Events (SAEs) 
 
Serious Adverse Event Definition. An SAE is any adverse event, without regard to causality, 
that is life-threatening or that results in any of the following outcomes: death; in-patient 
hospitalization or prolongation of existing hospitalization; persistent or significant disability or 
incapacity; or a congenital anomaly or birth defect. Any other medical event that, in the 
medical judgment of the Principal Investigator, may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the outcomes listed above is also 
considered an SAE. A planned medical or surgical procedure is not, in itself, an SAE.  
 
SAE Reporting Period. The SAEs that are subject to this reporting provision are those that 
occur from after the first dose of study medication through 28 days after discontinuation of 
study medication. Study staff will assist FDA or other regulatory staff in investigating any 
SAE and will provide any follow-up information reasonably requested. 
 
SAE Reporting Procedures. If an event is to be classified as a Serious Adverse Event 
(SAE), the following reporting procedures must be followed: 
 
• 
Code 3 event (with hospitalization, disability), reported to site IRB, all Site PIs (using 
Adverse Event Reporting Form below), NIH and the FDA (using MEDWATCH 
FORM) within 72 hours. 
• 
If Code 4 event, reported to site IRB, all Site PIs (using Adverse Event Reporting 
Form below), NIH and the FDA (using MEDWATCH FORM) within 24 hours. 
• 
Reports to the site’s IRB may use site-specific forms as needed. 
• 
Reports to other sites must use the Adverse Event Reporting Form below. 
• 
Reports to NIH and FDA must use the MEDWATCH 
(http://www.fda.gov/medwatch/index.html). The Medwatch form is submitted directly 
to the FDA and to the IRB.   
 
Contact Information: 
 


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Food and Drug Administration: Telephone 1-800-FDA-1088; Fax 1-800-FDA-0178; Internet 
http://www.fda.gov/medwatch/report.htm 
 
MedWatch: The FDA Safety Information and Adverse Event Reporting Program; Food and 
Drug Administration; 5600 Fishers Lane; Rockville, MD 20857-9787 
 
 
 
 
 


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Diagram of Protocol (To Guide Reporting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Step #1: Identify AE or Adverse Drug Event/Reaction  (Treatment Adverse event Checklist completed) 
2 
Adverse Event 
An untoward deviation from baseline health 
occurring from the time the patient signed consent 
1 
Adverse Drug Event or Reaction 
An untoward medical occurrence identified 
after initiating study treatments where there 
is a reasonable possibility that the event 
may have been caused by treatment 
 
Code 1      
 
 
Code 2     
 
Code 3    
 
Code 4 
Unrelated = not related   ** Unlikely = doubtfully related   ** Possible = may be related 
Probable = likely related   ** Definite = related 
Step #5: Determine if Event/Reaction is Serious Adverse Event/Reaction (Consult physician/PI and 
literature ) 
• 
Is life-threatening, disabling, or fatal?   
• 
Results in birth defect?    
• 
Requires serious medical/surgical intervention 
Step #6: Reporting Adverse Events/Reaction 
Code 4 
Within 24 hours, AE Form 
to:  
• IRB/DSMB,  
• Grant Agency & FDA 
Code 1 
Code 2 and 3  
No formal 
report 
required 
No hospitalization, not 
life-threatening, etc. 
Hospitalization, life-
threatening, etc. 
MD determines hospitalization is 
not related to study participation 
Site MD determines 
hospitalization, life-threatening 
event is related to study 
Step #2: Determine Severity of Event/Reaction (Treatment Side Effect Checklist will be completed) 
Step #3: Determine Cause of Event/Reaction (Consult physician/psychologist, PI and literature) 
Step #4: Determine if Event/Reaction is Expected (Consult physician, PI and literature) 
No formal report 
required 
No formal report required 
Within 3 calendar days, AE Form to:  
• 
IRB/DSMC,  
• 
Grant Agency & FDA 


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10.2. Auditing and Inspection 
The investigator will permit study-related monitoring, audits, and inspections by the IRB and 
University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11. Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
11.1. Consent Procedures 
All participants for this study will be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation in 
this study (See Participant Informed Consent Form).  This consent form will be submitted with 
the protocol for review and approval by the EC/IRB for the study.  The formal consent of a 
participant, using the EC/IRB-approved consent form, must be obtained before that participant 
undergoes any study procedure.  The form must be signed by the participant or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the 
consent. The investigator or designee will obtain informed consent before any study procedures 
occur, explaining all procedures in detail in an individual session. Participants will be assured 
that their participation is voluntary and that withdrawal from the study would not jeopardize 
current or future participation in research studies. All participants will be informed of potential 
risks and benefits involved in the study. 
12. Study Finances 
12.1. Funding Source 
The National Cancer Institute will provide funding for the conduct of this study. 
12.2. Conflict of Interest 
Any investigator with a conflict of interest (patent ownership, royalties, or financial gain greater 
than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict 
management plan.  All University of Pennsylvania investigators will follow the University of 
Pennsylvania’s conflict of interest policy. All Thomas Jefferson University investigators will 
follow Thomas Jefferson University’s conflict of interest policy  
12.3. Participant Payments 
Participants will be paid for their travel costs, time spent, and returned study medication blister 
packs. The maximum amount to be paid is $360-$375 for full participation (the $15 difference 
being based on whether the 24-week visit is in the clinic or either by telephone or at the 
hospital) and returning all of the study medication blister packs. The amount will be prorated 
based on the actual complement of study assessments completed and the number of study 
medication blister packs returned. Payments will be made at each in-person study visit and will 
include payments for telephone visits completed since the last in-person visit.  Participants will 


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also receive a baby gift of a box of 42 size 2 diapers and a tub of 40 baby wipes at either the 
Week 10 or the Week 24 visit (approximate value of $15 for both). Participants will also have the 
option to receive a cell phone with coverage for text and talk, at no cost. Payments will be made 
via Greenphire ClinCards. Clincards are reloadable prepaid cards that may be used for in-store 
purchases (by selecting either the “credit” or “debit” option) and online purchases.  Cash may be 
obtained using the ClinCard at a bank for no fee or at an ATM for a fee of up to $2.50.  
 
Table 3: Schedule of Participant Payments 
Visit 
Time Spent 
 
Travel Costs 
Return 
Medication 
Pack(s)& 
Phone 
 
Total for Visit 
Visit A: Screening (IP) 
$10 
$15 
 
$25 
Visit B: Baseline (IP/T) 
$60 
$15 
 
$75 
Visit C: Week 1 (IP) 
$35 
$15 
$1 
$51 
Visit D: Week 3 (T) 
$10 
 
 
$10 
Visit E: Week 5 (IP) 
$35 
$15 
$4 
$54 
Visit F: Week 7 (T) 
$10 
 
 
$10 
Visit G: Week 10 (IP) 
$30 
$15 
$5 
$50 
Visit H: Week 
24 
 Phone 
       or 
$45 
 
$45 
$0 
or 
 
$45 
Or 
 In-person 
$15 
$60 
Visit I: 2 Weeks postpartum (T) 
$10 
 
 
$10 
Visit J: 6 Weeks postpartum (T) 
$10 
 
Return 
Phone: $20 
$30 
Total payment for full 
participation 
$255 
$75 or $90 
$30 
$360 or $375 
IP=In-person, IP/T=In-person, +/- by telephone, T=By telephone, PP=Postpartum                                  
*$1 for each medication blister pack returned 
13. References 
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3. Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital 
statistics: 2004. Pediatrics 117(1):168-183, 2006. 
4. Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 13- to 16-
year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 
25(4):427-436, 2003. 


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5. Arias W, Viner-Brown S. Maternal smoking and birth defects in Rhode Island. Med 
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Clin Pharmacol Ther 79(6):600-608, 2006a. 
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clearance using cotinine and 3-hydroxy-cotinine spot saliva samples II. Model 
application. J Pharmacokinet Pharmacodyn 34(1):23-34, 2007. 
72. Ho MK, Mwenifumbo JC, Zhao B, Gillam EM, Tyndale RF. A novel CYP2A6 allele, 
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population of Black-African descent. Pharmacogenet Genomics 18(1):67-75, 2008. 
PMCID: 2910083 
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variation in nicotine-metabolizing enzymes. J Neurogenet 23(3):252-261, 2009, PMCID: 
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74. Schnoll RA, Patterson F, Wileyto EP, Tyndale RF, Benowitz N, Lerman C. Nicotine 
metabolic rate predicts successful smoking cessation with transdermal nicotine: a 
validation study. Pharmacol Biochem Behav 92(1):6-11, 2009. PMCID: 2657225 
75. Lee AM, Jepson C, Hoffmann E, Epstein L, Hawk LW, Lerman C, Tyndale RF. CYP2B6 
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62(6):635-641, 2007. 
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Appendix 
 
DATA AND SAFETY MONITORING PLAN (DSMP) 
 
 
 
TITLE: Placebo-controlled trial of bupropion for smoking cessation in pregnant women 
 
 
Principal Investigator(s): Henry Kranzler, M.D. 
 
 
 
Regulatory Sponsor: University of Pennsylvania 
 
 
Version #1 
 
 
Version Date: 7/6/2016 
 
 


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Monitoring 
The monitoring of a clinical trial is an essential element of study processes designed to ensure 
the protection of the subject’s rights, the safety of subjects enrolled in the trial and the integrity 
and quality of the resulting data. This Monitoring Plan (MP) describes the specifications for 
monitoring. This study monitoring is based on risk.  The study shall adhere to the requirements 
described in the protocol, the International Conference on Harmonization (ICH) and FDA Good 
Clinical Practice (GCP), and Sponsor SOPs. 
 
Sponsor Monitor 
The Sponsor will appoint a qualified Monitor to review and evaluate study data and activities.   
The Sponsor will provide a monitoring plan and associated documents (protocol, Informed 
Consent Form (ICF), Standard Operating Procedures (SOPs), and an Investigator’s Brochure 
(IB) to the Monitor.  The Monitor will be qualified by education, experience, and training of Good 
Clinical Practice requirements as well as regulatory compliance.  The Sponsor will evaluate any 
financial conflict and will ensure resources are available to carry out monitoring activities.  
Training with the protocol, CRFs, ICF, and DSMP will be provided by the Regulatory Sponsor 
prior to study commencement.  The Sponsor is responsible to ensure that appropriate 
monitoring is occurring as per regulations, 21 CFR 312.50 and 312.56. 
 
DSMB 
In addition to the Sponsor Monitor, a DSMB will be utilized based on the risks associated with 
the study.   
 
The DSMB is a group of individuals who are independent from the study team and are charged 
with providing expertise and recommendations based on the real time review of trial related 
data.  The DSMB shall review the Monitoring Plan prior to study initiation and accept or provide 
comments to the Sponsor.   
 
• 
The DSMB reviews study data for subject safety, study conduct and progress, and efficacy.  
The DSMB can make recommendations concerning the continuation, modification, and/or 
termination of the study.   
• 
The Sponsor selects each member of the DSMB.  In selecting members to serve on a 
DSMB, consideration of each person’s relevant expertise, experience in clinical trials and in 
serving on other DSMBs, and absence of serious conflicts of interest is necessary.  
Members of the DSMB must have no direct involvement in the conduct of the study.  Each 
member’s qualification will be documented. 
 
Monitoring Plan 
This monitoring plan lists the approach to monitoring the clinical trial and is risk-based. Sponsor 
oversight focuses on activities to prevent or mitigate important and likely risks to data quality 
and to processes critical to human subject protection and trial integrity.   
 
Monitoring activities include: 
• 
Oversight of Investigator conduct, including supervision of study site staff and data reporting 
• 
Review of the  study site’s processes and procedures (e.g., process for investigational 
product administration) 
• 
Review of site records for completeness and accuracy  
• 
Ongoing evaluation of safety data and the emerging benefit-risk profile of an investigational 
product 
• 
Review of recruitment rates  


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• 
Review of protocol deviations and non-compliance 
• 
Review of subjects who dropped out 
• 
Review of the timeliness of data collection and submissions to the Sponsor 
• 
Verification  that informed consent was obtained appropriately 
• 
Verification of adherence to the protocol, including  eligibility criteria, study test and 
procedures, investigational product accountability 
• 
Verification of the disposition of the investigational product 
• 
Review of evaluation, assessment, documentation and reporting of Adverse Events 
• 
100% source data verification will be performed for all subjects. 
 
Requirements for communicating monitoring results: 
The Study Monitor shall share Monitoring visit reports (MVRs) with the Sponsor/Investigator.  
Safety concerns will also be shared with the Sponsor/Investigator.  Within 10 business days of a 
monitoring visit, the Monitor will prepare the Monitoring Visit Report (MVR) and submit it to the 
Sponsor. 
 
Managing non-compliance: 
Any non-compliance issues arising will be managed in working with the study Investigators.  
 
Ensuring Quality Monitoring: 
The Sponsor will meet with the Monitor twice a year, following the monitoring visit, to ensure 
quality monitoring. 
 
The investigational product, bupropion has a greater than minimal risk safety profile for the 
mother.  Prior experience in human and animals raises safety concerns.  The risks associated 
and potential safety concerns inherent to the study are that bupropion commonly causes dry 
mouth, insomnia, and dizziness.  Other common adverse effects of bupropion runny nose, neck 
pain, loss of appetite, nausea and vomiting, rash, itching, dry skin, sweating, tremor, abdominal 
pain, constipation, agitation, muscle or joint pain, urinary frequency, sleepiness, abnormal 
thinking, bronchitis, hives, strange taste in the mouth, weakness, fever, headache, depression, 
irritability, and blurred or double vision.  Rare, but serious, complications that may be related to 
bupropion include seizures or hypomania. 
 
For the developing fetus, there is a greater than minimal risk safety profile. Preclinical data 
indicate that bupropion administered orally to rats and rabbits at doses up to 450 and 150 
mg/kg/day, respectively, showed no clear evidence of teratogenic activity. A slightly increased 
incidence of fetal malformations and skeletal variations were observed in rabbits. Decreased 
fetal weights were seen at doses of 50 mg/kg and greater.  In another study, rats administered 
bupropion at oral doses of up to 300 mg/kg/day throughout pregnancy and lactation produced 
offspring showing no apparent adverse developmental effects.  One retrospective study 
examined 7,005 antidepressant-exposed pregnancies in a managed-care database. The study 
showed no greater risk for congenital malformations among the 1,213 bupropion-exposed first-
trimester pregnancies than for other first-trimester antidepressant exposures or to bupropion 
use during the second or third trimesters.  
 
Enrollment will take place at the University of Pennsylvania and Thomas Jefferson University.   
 
For all subjects consented the Monitor will perform:  
• 
Review of informed consent form (ICF) and informed consent process  
• 
Verification of eligibility (i.e., review of inclusion/exclusion criteria)  


Bupropion Study 
 
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sponsor 
• 
Assessment of treatment compliance  
• 
Review of subject evaluations, testing and follow-up per the protocol  
• 
Assessment and follow-up of safety issues  
• 
Review and comparison of source documents and CRFs for completion and accuracy  
• 
Investigational agent accountability and adherence to product labels  
• 
Review any regulatory documents for amendments/modifications/updates 
 
 
Timing and Frequency of Monitoring Visits: 
On-site monitoring activities will occur based on the high level of risk in the study. Monitoring 
visits will be done twice each year that the study is active. 
 
The first monitoring visit will be held no later than four weeks (and no earlier than two weeks) 
after the baseline visit of the first subject in any new site added.  Subsequent monitoring visits 
will take place twice each year. 
 
A study closeout visit at each active site will be conducted no later than 1 month after the final 
subject has completed the study at that site. 
 
Review of the Informed Consent Form  
Review the ICFs to verify that consent was obtained in accordance with regulations and 
guidelines. 
  
Regulatory Document Review  
The site regulatory documents will be maintained in the site regulatory binder. The regulatory 
binder will be reviewed by the Monitor at each monitoring visit. The Monitor will review the 
binder to ensure its completeness and that study documents are filed appropriately in a timely 
manner. 
 
Adverse Event (AE) and Serious Adverse Event (SAE) Reporting  
AEs: The Monitor will confirm during review of the collected data and source 
data/documentation that AEs have been reported as required by the FDA.   
 
SAEs: All will be reported to the Sponsor using MedWatch or CIOMS forms and submitted to 
the corresponding IRB as per that committee’s requirements.  
 


Bupropion Study 
 
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sponsor 
14.2 ClinCard Data Security and Privacy Statement (dated 14 January 2016)  
Confidentiality of Protected Health Information (PHI)   
All clinical trial participant information is stored securely. Greenphire does not sell, use or 
distribute clinical trial participant information for any purpose other than those needed to 
execute, service and maintain the ClinCard program (including ClinCard Direct Deposit and 
Travel Reimbursement methods).  
Greenphire protects the privacy of Electronic Protected Health Information (“EPHI”), disclosed 
or provided to us in compliance with the Security Standards for the Protection of Electronic 
Protected Health Information at 45 CFR Sections 160 and 164 (the “Security Rules”). Towards 
that end, Greenphire has implemented administrative, physical, and technical safeguards 
(detailed below) that reasonably and appropriately protect the confidentiality, integrity, and 
availability of EPHI; ensures that any agent or subcontractor to whom we provide EPHI agrees 
to implement reasonable and appropriate safeguards to protect it; and will report any Security 
Incident involving EPHI of which it becomes aware within five (5) days of learning of the Security 
Incident.  
Data Information Security  
As a matter of policy and commitment to clients and clinical trial participants, Greenphire takes 
great strides to protect all information relating to cardholders. Greenphire has deliberately 
designed its payments and communication platform including all of Greenphire’s externally 
facing web tools to actively protect all data transfers and data stored with Greenphire’s 
infrastructure:  
Database and Encryption– All passwords within our database are protected using the one-
way SHA1 algorithm to encrypt passwords, which are then encrypted by the one-way 
MD5 algorithm. Where necessary, Greenphire’s platform makes use of encryption using 
the 256 bit Advanced Encryption Standard (AES or otherwise known as Rijndael), which 
is one of the most popular algorithms used in symmetric key cryptography. AES is 
approved by the US National Intelligence Agency (NSA) for top secret information.  
Web Tools – All of Greenphire’s web tools that are involved in transferring data between an 
end-user's web browser and Greenphire’s platform (and vice versa) are secured by 256 
bit Secured Socket Layer (SSL) with TLS 1.2 encryption. Greenphire is able to track the 
activities performed on accounts by site administrators through a system of unique 
logins which allow users access to the clincard.com web tool. In addition, all user 
activities in the Greenphire Platform are auditable.  
Financial Data Transfer - Communications between the Greenphire platform and financial 
networks are executed via Web Service (API) or sFTP transport.  
Physical Protection – Greenphire houses its internal database on servers that are located 
in a highly secure, off-site facility. Access to the physical servers at the facility is limited 
to Network Operations Center (NOC) Engineers and Technicians. The facility is secured 
with a bio-metric security system that can track access to the facility and is monitored by 
digital security video surveillance, includes multiple suppliers for network connectivity 
and redundant power supplies including on-site power generation in the event of 
emergency.  
Authorized Access – Greenphire restricts access to sensitive data to only a limited number 
of essential internal personnel. Authorized individuals are only permitted to access data 


Bupropion Study 
 
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sponsor 
if it is required to service our client, their authorized users or the clinical trial participant. 
The number of authorized individuals remains limited to protect against internal threats 
to the security of sensitive data.  
Proactive Design - Greenphire’s internal technology platform has been intentionally 
designed to exclude the requirement of certain sensitive information that other similar 
companies require to be stored in their systems, such as PIN numbers. If new types of 
sensitive data must be introduced and stored, per the design of a specific protocol, 
Greenphire will protect the data using the encryption methods described previously.  
Customer Service - Greenphire provides all of its cardholders with 24/7/365 customer 
service. Customer service is handled by both an automated IVR system and a call 
center where live customer service representatives may provide financial assistance to 
cardholders. Customer service functionality is intentionally kept separate from 
implementation and client support and, consequently, no information is shared with 
customer service representatives related to the protocol, sponsor, structure of the trial, 
medical indication or other potentially sensitive information.  
Quality Control Process - Greenphire’s Quality Control (QC) Department performs system 
testing in an isolated environment to test and ensure that the software is functioning 
properly. Each new piece of functionality is thoroughly tested individually. In addition, QC 
conducts integration and regression testing before new code is approved for movement 
into production. When a change to the system necessitates a change to the database, 
the required changes and process to make the changes are documented and tested 
prior to being performed on production. No code is pushed to production until it has 
passed QC testing. Data used in QC is test data and does not include data that is, or 
ever was, production data.  
Safe Harbor  
Greenphire has voluntarily obligated itself to the jurisdiction of the U.S. Department of 
Commerce by self-certifying to the Safe Harbor framework necessary to receive personal data 
from companies doing business in the European Union and Switzerland.  
Further information regarding the U.S. – EU and U.S. - Swiss Safe Harbor Frameworks is 
available at export.gov/safeharbor/index.asp 

ICF_001.pdf: 
DATE:
14-Jun-2019
Institutional Review Board
TO:
Henry R Kranzler
3800 Spruce St., First Floor Suite 151
CC:
Pond, Timothy
Zindel, Leah
Philadelphia, PA 19104
Phone: 215-573-2540
(Federalwide Assurance # 00004028)
RE:
IRB PROTOCOL#:
820364
PROTOCOL TITLE: Placebo-controlled trial of bupropion for smoking cessation in pregnant women
(PRIME)
SPONSOR:
National Cancer Institute/NIH/DHHS
REVIEW BOARD:
IRB #1
IRB AMENDMENT: NOTICE OF APPROVAL
Dear Dr. Kranzler,
The documents noted below, for the above-referenced protocol, were reviewed by the
Institutional Review Board using the expedited procedure set forth in 45 CFR 46.110 and
approved on 13-Jun-2019.
This study has been determined to pose greater than minimal risk to subjects. IRB approval
for the study will expire on 10-Mar-2020.
The documents included with the application noted below are approved:
-HS-ERA Modification Submission, confirmation code: cjbgjcgd, submitted 06/07/2019
-Cover letter, Version 24, dated 6/7/2019
-Protocol, Version 24, dated 6/5/2019, tracked and clean
-Informed Consent form, Version 24, dated 6/7/2019, University of Pennsylvania subjects,
tracked and clean
-Modification form, Version 24, dated 6/7//2019
-Cover letter, dated 6/13/2019 containing the list of documents for this submission
ONGOING REQUIREMENTS:
You must obtain IRB review and approval under 45 CFR 46 if you make any changes
to the protocol, consent form, or any other study documents subject to IRB review
requirements. Implementation of any changes cannot occur until IRB approval has
been given.
Reportable event, such as serious adverse events, deviations, potential unanticipated
problems, and reports of non-compliance must be reported to the IRB in accordance
with Penn IRB SOP RR 404.
When enrolling subjects at a site covered by the University of Pennsylvania’s IRB, a
copy of the IRB approved informed consent form with the IRB approved from/to
stamp must be used unless a waiver of written documentation of consent has been
granted.


 
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UNIVERSITY OF PENNSYLVANIA 
INFORMED CONSENT AND HIPAA AUTHORIZATION FORM 
Protocol Title:   
Placebo-controlled trial of bupropion for smoking 
cessation in pregnant women 
Protocol Number: 
820364 
Principal 
Investigator: 
Penn: Henry R. Kranzler, M.D. 
Treatment Research Center,  
3535 Market St., Suite 500 Philadelphia, PA 19104 
(215) 746-1943 
 
 
Study Contact: 
Penn: Leah Zindel, Study Coordinator  
(215) 746-1954 
 
 
Emergency 
Contact: 
 Emergency Pager 
 (215) 505-3799 
Why am I being asked to volunteer? 
You are being invited to participate in this study, Placebo-controlled trial of bupropion for smoking 
cessation in pregnant women, because you are pregnant and currently smoke cigarettes. The 
overall duration of the study is four and a half years, but your participation is expected to last only for 
six months from the time you first attempt to quit smoking. Approximately 360 women will be recruited 
for this study, with approximately 180 of them coming from the Hospital of the University of 
Pennsylvania (HUP) other UPenn facilities, or Thomas Jefferson University.   
Your participation in this study is voluntary, which means that you can choose whether to participate 
or not. If you choose not to participate, there will be no loss of benefits to which you are otherwise 
entitled. Before you can make your decision, you will need to know what the study is about, the 
possible risks and benefits of being in this study, and what you will have to do in the study. The 
research team is going to talk to you about the research study, and they will give you this consent 
form to read.  You may also want to discuss it with your family, friends, or doctor. You may find some 
of the medical language difficult to understand. Please ask the study doctor and/or the research team 
about this form. If you choose to participate, you will be asked to sign this form. You will have a 
chance to ask any questions that you may have before you sign this consent form.  You will receive a 
copy of the signed consent form to keep.   
It is important for pregnant smokers to quit smoking because it reduces both their risk for health 
problems and problems that their babies may experience. Bupropion is approved by the US Food and 
Drug Administration (FDA) for smoking cessation in people who are not pregnant, but there are no 
carefully controlled studies on the use of bupropion to help pregnant women quit smoking.  Before 
being approved to help people quit smoking, bupropion was approved to treat depression.  It has 
been used for that purpose in pregnant women, but has not been formally tested for that purpose.   
 
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Quitting smoking can be difficult for pregnant women.  Although the best situation would be for 
pregnant women to quit smoking without the use of medications, bupropion may be helpful for 
pregnant women who cannot quit on their own.  
While taking part in this study you will be randomly assigned (like the flip of a coin) to receive 
bupropion or a placebo (a harmless, inactive substance) to help you quit smoking. Your chance of 
getting the bupropion or placebo is 50/50. This study is a double-blind study, meaning that neither the 
study staff nor you will know if you are getting the bupropion or the placebo. In addition to receiving 
the study medication, you will receive counseling on four occasions during your pregnancy and twice 
after the pregnancy to help you stop smoking or continue not to smoke. During the 10 weeks of 
treatment with bupropion or placebo, you will also receive a daily text message in the morning to 
remind you to take the medication and a text message in the evening to ask if you took the medication 
that day. You will also be offered the use of a cell phone with unlimited talk and text, but no data, to 
allow you to receive the text messages, participate in phone counseling sessions, and to contact 
study personnel during the study. There is no charge for this phone and you are not required to take 
it. You will be asked to return the phone to the study staff at the end of the study. 
A note about the phones: 
•
The phones will be provided for the duration of the study, and will include unlimited domestic
talk and text.
•
International calls and text are not permitted.
•
You will not be responsible for the cost of the phone if it is lost.
•
The phones are to be returned if you withdraw from the study.
•
The phones are to be returned at the end of the study, at which time the information contained
on the phones will be electronically ‘wiped.’
•
The phones will be deactivated at the end of the study.
What is the purpose of this research study? 
1. To determine whether bupropion is better than a placebo (a harmless, inactive substance) in
helping pregnant women to quit smoking.
2. To evaluate the health effects of bupropion compared to placebo (a harmless, inactive substance)
on pregnant women and their babies.
3. To evaluate the effects of bupropion compared to placebo (a harmless, inactive substance) on
depressive symptoms and cigarette craving in pregnant women.
4. To examine whether your genotype (your unique DNA makeup) determines your bodily functioning
and behavioral responses to bupropion. People may respond to bupropion in part based on
differences in what they inherit from their parents.  We will examine genes (made up of DNA) that are
thought to be involved in the effects of bupropion. In addition, we plan to test genetic markers to
identify genes that influence other behaviors and characteristics that we will ask you about and that
are being measured as part of this research.  We will also use your DNA to study differences in genes
between groups of people, because these differences can help in understanding the role of genes in
risk for different disorders among groups of people. Because the DNA analysis is a key part of the
study, if you choose not to provide blood for a DNA sample, you may not be able to participate in the
study.
How long will I be in the study? How many other people will be in the study? 
You will be in the active phase of the study for 10 weeks and will have 3 follow-up visits: one about 24 
weeks after you first attempt to quit smoking and one at 2 and at 6 weeks after your baby is born.  
Thus, the total time that you would be in the study is about 6 months.  It is expected that, a total of 
360 participants will participate in the study. 
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What am I being asked to do? 
You are being asked to complete assessments in person and by phone and allow us to review your 
medical record and your baby’s medical records after he or she is born.  You will also be asked to 
give a blood sample (3 tubes, enough to fill 1.5 tablespoons), take a study medication for 10 weeks, 
set a date to quit smoking, and try to quit.  Finally, you’ll be asked to come back for 3 visits after the 
10-week medication study.  Overall, during the study, you’ll be asked to attend a total of 10 visits, six 
of which will be in person and four will be done by telephone.  The specific procedures are detailed 
below. 
What procedures are involved with participation in this research study? 
Visit A: Screening Visit:  After you review this form and have all of your questions answered, you will 
be asked to sign the form.  You will then be asked to provide the researchers with information to 
determine whether you are eligible to participate in the study.  By signing this form, you also give us 
permission to review your medical record to obtain information on your medical history, smoking, and 
other substance use.  Your signature on this form will also allow us to obtain information from your 
baby’s medical record following delivery.  We will use that information to see whether bupropion and 
smoking cessation reduce problems later in pregnancy and during delivery.   
On this visit, you will be interviewed for about an hour at the clinic where you are receiving prenatal 
care.  This interview will include questions about your medical and pregnancy history, and any mood 
or other symptoms that you may have. We will also ask you about any past or current use of alcohol, 
drugs, and cigarettes. During this visit, and all other in person visits, we will ask you to blow into an 
instrument that measures a chemical (carbon monoxide) that is in tobacco smoke. 
If your date of delivery has not been estimated by ultrasound, we will ask you to have an ultrasound 
test to provide an accurate estimate of when your baby will be born.   
 
If you are deemed eligible and decide to participate, we will also ask you to provide the names and 
contact information of people (trusted friends or family members) who may serve as additional 
contacts if we cannot locate you for safety or other study-related reasons. We will only tell them that 
you are in a study and that you gave us their names to help us contact you, if we are unable to reach 
you during the study. 
 
If you are eligible for this study, the following things will happen: 
Visit B: Baseline Visit:  This in-person visit will be completed within 30 days of your screening visit and 
will last approximately 90 minutes.  At the visit, we will measure your heart rate and ask you to 
complete seven questionnaires by telephone and in person. We will ask you to provide a blood 
sample (3 tubes, enough to fill 1.5 tablespoons) to be used to conduct genetic testing and to measure 
your body’s ability to break down nicotine, which is contained in cigarettes. 
You will then receive the first of six counseling sessions in the study.  This first, “pre-quit” counseling 
session will last 30 minutes and will help to prepare you to quit smoking. With your permission, we will 
make an audio recording of this and all other counseling sessions that you receive during the study.  
These recordings will be deleted after they have been reviewed to ensure that study personnel have 
followed correct counseling procedures. 
  
You will be given study medication at this visit and will be instructed to begin taking it the following 
morning.  You will be asked to identify a quit date within a week of beginning the study medication. 
You will start the study medication by taking one capsule (150 mg/day or placebo, a harmless, 
inactive substance) each morning for the first 3 days and then one capsule each morning and each 
evening (150 mg twice daily) for the remainder of the 10-week study treatment period.  At this visit, 
and at every visit while you are taking the study medication, you will be asked about any side effects 
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that you may have experienced from the study medication. We will also ask you to return all study 
medication that you have not taken and the study medication packaging. 
At this visit, you will also be offered a cell phone (if you choose this option) to be used for the text 
messages, phone counseling visits and for reminder calls. You may not use the phone for 
international calls. At the end of the study, you will be expected to return the phone to study staff. The 
day after the Baseline Visit, you will begin to receive two daily text messages.  The first message of 
the day (in the morning) will concern the expected development based on your baby’s age, 
accompanied by a reminder to take your study medication.  The second message of the day (in the 
evening), will ask you whether you took all of your study medication that day.  You’ll be asked to text 
back indicating that you received the message (in the morning) and whether you took the medication 
that day (in the evening).  We will ask you which times you would like to receive the text messages 
each day.   
Although the responses that you send us via text messages will help us to keep track of your 
participation, the inbox for our texting center is not monitored, so if you have any study-related 
questions or concerns, please call our study staff to speak with them directly, rather than texting them.  
Text messaging should not be used in emergency situations; for emergencies, you should instead call 
911. 
Visit C: Quit Date Visit:  Your scheduled quit date visit will occur approximately one week after the 
baseline visit and will last approximately 45 minutes. During this visit, we will measure your heart rate 
and you will be asked to blow into an instrument that measures a chemical (carbon monoxide) that is 
in tobacco smoke. The study nurse or coordinator (trained and supervised by the nurse, psychologist, 
or physician) will collect any medication that you had not taken and the study medication packaging. 
You will receive a four-week supply of study medication and a study nurse or coordinator will ask you 
about any study medication side effects that you may have experienced since starting the study. You 
will also be asked to complete two questionnaires and will receive 20 minutes of “quit-day” counseling, 
which will help you to identify things that could cause you to return to smoking and to develop a plan 
to avoid tempting situations.     
Visit D: Week 3:  This visit will occur by telephone and will last approximately 25 minutes, during 
which time you will be asked to complete one questionnaire over the telephone.  You will be asked 
about your cigarette use since the last visit and any medication side effects you may have 
experienced.  You will also receive 10 minutes of counseling by phone to help you avoid smoking or, if 
you need to, set another quit date to try again to quit smoking. 
Visit E: Week 5:  This in-person visit will last approximately 30 minutes.  You will be asked to 
complete two questionnaires and be interviewed about your cigarette use since the last visit.  We will 
measure your heart rate and you will be asked to blow into an instrument that measures a chemical 
(carbon monoxide) that is in tobacco smoke. You will be asked to provide a blood sample (2 tubes, 
enough to fill 1 tablespoon) to be used to measure concentrations of study medication in your blood. 
The study nurse or coordinator (trained and supervised by the nurse, psychologist, or physician) will 
collect any medication that you have left and the study medication packaging. You will receive a five-
week supply of study medication and a study nurse or coordinator will ask you about any study 
medication side effects that you may have experienced since starting the study and assess any 
changes to your mood. You will also receive 10 minutes of counseling to help you avoid smoking or, if 
needed, set another quit date to try quitting again. 
Visit F: Week 7:  This telephone visit will last approximately 15 minutes and you will be asked to 
complete one questionnaire. You will also be asked about your cigarette use since the last visit and 
any medication side effects you may have experienced. 
Visit G: Endpoint visit:  This in-person visit will last approximately 25 minutes.  You will be asked to 
complete two questionnaires and about your cigarette use since the last visit. During the visit we will 
measure your heart rate and you will be asked to blow into an instrument that measures a chemical 
(carbon monoxide) that is in tobacco smoke. The study nurse or coordinator (trained and supervised 
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by the nurse, psychologist, or physician) will collect any medication that you had not taken and the 
study medication packaging. The study nurse or coordinator will ask you about any study medication 
side effects that you may have experienced since starting the study and assess any changes in your 
mood.  
Visit H: Week 24 after the Quit Date:  About six months after you started treatment, you will be 
contacted by telephone or by letter to remind you that your Week 24 visit is coming up.  During this  
visit, which may be conducted by phone or in person, a research technician will complete one 
questionnaire with you and ask you about your cigarette use since the last visit.  When the visit is in 
person, she will also ask for a carbon monoxide breath sample. If your Week 24 visit comes at about 
the same time that you deliver your baby, the study coordinator will see you in the hospital for this 
visit. If it comes at about the same time as your 6-week check-up with your doctor, the study 
coordinator will arrange for the visit to be on that day. Because the carbon monoxide breath sample is 
an important part of the study, the nurses at the hospital may ask for a breath sample at the time that 
you deliver and at the time of your office visit after the baby is delivered.  
Visits I and J: 2 and 6 weeks after delivery:  The last two sessions will be held by telephone after the 
birth of your baby.  You will be asked to complete several questionnaires, similar to those completed 
previously.  You will also receive 10 minutes of counseling over the phone. 
 
What are the possible risks or discomforts?  
Bupropion can cause two different kinds of risks: the risk to you (from the medication and from the 
blood sample collection) and the risk to your developing baby (from the medication).  
 
What are the possible risks of bupropion to you? 
Bupropion is an antidepressant medication that is also approved to help people quit smoking.  
 
The Most Common Side Effects that you may experience are dry mouth (11%), insomnia (31%), and 
dizziness (8%).  
 
Other Likely Side Effects (occurring in at least 1% of patients) include: runny nose; neck pain; loss of 
appetite; nausea and vomiting; rash; itching; dry skin; sweating; tremor; abdominal pain; constipation; 
agitation; muscle or joint pain; urinary frequency; sleepiness; abnormal thinking; bronchitis; hives; 
strange taste in the mouth; weakness; fever; headache; depression; irritability; and blurred or double 
vision. 
.  
Unlikely Side Effects (occurring in less than 1% but greater than 0.1% of patients): include: bruising; 
swelling; back pain; chills; hernia; increased sensitivity to light; flushing; migraine; a drop in blood 
pressure on standing; heart pounding or racing; stroke; abnormal liver function; tooth grinding;  trouble 
swallowing; increased stomach acid; inflammation of the lips, gums or tongue; jaundice; leg cramps 
and twitching; abnormal coordination; confusion, decreased interest in sex; decreased memory, a 
sense of feeling not yourself; rapid changes in mood; hostility; increased muscle tone; parkinsonism; 
decreased feeling or a tingling feeling in extremities; suicidal ideation; acne; difficulty focusing vision; 
dry eyes; excessive abnormal movement, over excitation; and an increased frequency or urge to 
urinate. 
Rare but Potentially Serious Side Effects (occurring in less than 0.1% of patients) include: feeling ill; 
fainting; memory loss; feeling unreal; hypomania (increased activity level combined with a “high” 
mood and decreased need for sleep); loss of balance; and spasm of the airways. Bupropion has also 
been reported to cause seizures in rare instances. This has been reported in less than 0.1% of people 
taking the medication. You should not take bupropion if you have a history of seizure disorder 
(epilepsy) or if you ever had bulimia or anorexia nervosa, because Bupropion is more likely to cause 
seizures in people with these conditions.  
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Effects on Mood: When bupropion is used for quitting smoking, it can cause you to have serious mood 
changes.  These include depression or mania (an extreme increase in mood and activity and a 
decreased need for sleep), hallucinations, paranoia, delusions, thoughts of killing someone, hostility, 
agitation, aggression, anxiety, and panic, as well as thinking about suicide, attempting suicide, and 
actually committing suicide.  These effects may or may not be related to the stress of quitting 
cigarettes.  
You should contact the study doctor immediately if you experience any of these symptoms: thoughts 
about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, 
feeling very agitated or restless, panic attacks, trouble sleeping, new or worse irritability, acting 
aggressive, being angry, or violent, acting on dangerous impulses, an extreme increase in activity and 
talking or any other unusual changes in behavior or mood. We will also monitor you carefully for these 
symptoms. 
 
What are the possible risks of bupropion to your developing baby? 
The use of bupropion for quitting smoking in pregnant women has not been well studied.  There is a 
risk that bupropion could adversely affect your baby. Bupropion is classified by the FDA as 
“Pregnancy Category C,” meaning that although animal studies have shown an adverse effect on the 
developing fetus, there are no well-controlled studies in humans, and the potential benefits of use 
during pregnancy may outweigh the risks. 
Bupropion given to rats and rabbits at doses between 30 and 100 times those to be used in this study 
showed no clear evidence of birth defects. A slightly increased incidence of birth defects and skeletal 
variations were observed in rabbits. Decreased fetal weights were seen at 10 times the doses that will 
be used in this study. In another study, rats given bupropion at oral doses of up to 70 times the dose 
to be used in this study throughout pregnancy and lactation produced offspring showing no apparent 
birth defects.  
No study has specifically tested bupropion for the treatment of either depression or quitting smoking in 
pregnant women. One study looked at the medical records of more than 7,000 women who took 
antidepressants during pregnancy.  The review showed no greater risk for birth defects among the 
more than 1,000 women who took bupropion during the first trimester than women who took other 
antidepressants during the first trimester or who took bupropion during the second or third trimesters. 
In another study that reviewed the medical records of women who took medication during pregnancy, 
there was an increased risk of cardiac malformations among women who took bupropion during the 
first trimester (three months) of pregnancy.  To lessen any risk to your developing baby, we will not 
begin treatment until after the first trimester of pregnancy. 
 
Are there risks associated with taking the placebo medication? 
Each placebo capsule contains 120 mg of calcium, which taken twice a day as part of the study, is 
less than the equivalent of the calcium contained in a single glass of milk.  Your obstetrician may have 
recommended a calcium supplement as well.  Therefore, if you plan to take a calcium supplement in 
addition to what is prescribed by your obstetrician, please discuss it with the study staff, as too much 
calcium could cause a problem with your kidneys.     
 
What are the possible risks of a blood draw? 
There will most likely be some mild discomfort from the blood draw. Some people develop a bruise at 
the needle site; some people report dizziness after the blood is drawn, which can cause fainting; and, 
some people develop minor infections.  To prevent you from falling, you will be seated at the time 
blood is drawn and will be permitted to lie down if you feel faint.  To prevent infection, the area where 
the needle is to be inserted will be wiped with a disinfectant before and after the needle is inserted. 
Only sterile needles will be used. The puncture site will be covered with a bandage. Sometimes we 
may not be able to draw blood at the first visit. We will try again at the Week 5 visit. If we still cannot 
get blood at that visit, we will not keep trying. We will obtain DNA from your saliva instead. 
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Risks Related to Genetic (DNA) Testing:   
The principal risk of genetic testing is breach of confidentiality, with sensitive information concerning 
your genetic risk for disease becoming known.  Such information, if available to you, could cause 
distress and if available to health or life insurers could adversely affect your access to insurance or its 
benefits.   
A recent federal law, called the Genetic Information Non-Discrimination Act (GINA), helps reduce the 
risk from health insurance or employment discrimination. The law does not include other types of 
misuse by life insurance or long term care insurance. If you want to learn more about the GINA law, 
you can find the information on the internet or ask our study staff. Our study staff will provide you with 
a GINA law handout, which includes an internet web link.  
Variation in some genes is known to be directly related to risk for certain illnesses, and other genes 
we may study in your DNA may be shown at some point in the future to be related to illness.  Certain 
genetic research may reveal that you are at risk for certain diseases or that you are a carrier of a 
genetic disorder.  This could mean that you or members of your extended family may have an 
increased likelihood of developing the disorder, or may be carriers.   
Safeguards To Be Taken:  To guard against these risks, you will not be provided with genetic test 
results and your confidentiality will be closely protected. All study information will be kept in a research 
record that is separate from your medical record and not available to insurance companies.  We will 
not make any of our genetic findings available to you, nor will we add them to your medical record. (If 
you want to know your risk for genetic diseases, we will refer you to a genetic counselor.)  We hope 
that this will prevent any information that could cause you trouble in the future from becoming known 
to anyone other than the scientists working on this study. While we cannot foresee situations where 
we would be forced to reveal potentially sensitive information about you (despite our efforts to 
maintain confidentiality), or where people who should not have this information could obtain it, it is 
possible that presently unforeseen situations may arise where this could happen.   
Privacy concerns with text messages:  The primary privacy concern with using text messages in a 
health context is that the messages can be intercepted by someone other than the person for whom 
they were intended.  The text messages are not encrypted and may be read or accessed by others on 
your phone. 
We will use the following methods to reduce the risk of your text messages being misused: 
• 
You will be asked to approve your participation in the text messaging.  To confirm your 
willingness to participate in the text messaging, you will be asked to respond to a text 
message confirming that you want to participate and confirming your phone number. 
• 
We will also address with you how you may adjust the settings on your phone to limit 
information shown in text message alerts, and how you may delete private messages after 
they are read and/or sent.  We store all information that identifies you, on a server in a manner 
that is compliant with legal requirements for confidentiality and privacy. Information transmitted 
through text messaging may be stored by your cell phone service provider in accordance with 
its privacy policy. 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to you.  This 
includes information that, once learned, might cause you to change your mind about being in the 
study.  We will notify you as soon as possible if such information becomes available. 
 
What are the possible benefits of the study?  
1. The counseling, text message reminders, and study medication may help you quit smoking. 
2. Quitting smoking may improve your health and the health of your unborn child. 
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3. The knowledge obtained from this study may benefit other health care providers or pregnant 
smokers who decide whether to use bupropion to quit smoking during pregnancy. 
4. You may not have any benefit while taking part in this study. 
 
What other choices do I have if I do not participate in the study?  
1. You can try to quit smoking on your own, without the use of bupropion or placebo. 
2. You can receive care from your health care provider to quit smoking. 
3. You may choose not to participate and not receive smoking cessation treatment.   
 
Will I be paid for being in this study? 
You will be paid for your travel and time, and for returning your study medication packagings, as 
described below.  You will also be offered the use of a cell phone with coverage for text and talk, if 
you choose this option, at no cost to you. At the end of the treatment period, you are expected to 
return the phone to study staff. You will be paid $20 when you return the phone. Payments will be 
made to you with a Greenphire ClinCard. A Greenphire ClinCard is a reloadable, prepaid card that 
may be used for in-store purchases (by selecting either the "credit" or “debit" option), online 
purchases, in an ATM to get cash, and for cash advances at a bank (though there are fees associated 
with ATM withdrawals or bank cash advances). The study doctor or other staff member will tell you 
more about when you will get paid and provide you with an information sheet about how to use the 
Greenphire ClinCard. Funds added to the card should be available immediately, however in some 
cases it may take up to 1 business day. If you lose the card, please contact our study staff 
immediately. The study coordinator can cancel the original card and reissue a new card to you. 
 
Visit 
Time Spent 
 
Travel Costs 
Return 
Medication 
Pack(s)& 
Phone 
 
Total for Visit 
Visit A: Screening (IP) 
$10 
$15 
$25 
Visit B: Baseline (IP/T) 
$60 
$15 
$75 
Visit C: Week 1 (IP) 
$35 
$15 
$1 
$51 
Visit D: Week 3 (T) 
$10 
 
 
$10 
Visit E: Week 5 (IP) 
$35 
$15 
$4 
$54 
Visit F: Week 7 (T) 
$10 
 
 
$10 
Visit G: Week 10 (IP) 
$30 
$15 
$5 
$50 
Visit H: Week 
24 
 Phone 
       or 
$45 
 
$45 
$0 
or 
 
$45 
Or 
 In-person 
$15 
$60 
Visit I: 2 Weeks postpartum (T) 
$10 
 
$10 
Visit J: 6 Weeks postpartum (T) 
$10 
 
Return Phone: 
$20 
$30 
Total payment for full 
participation 
$255 
$75 or $90 
$30 
$360 or $375 
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The maximum amount that you will be paid is $375 for full participation, including an in-person visit at 
Week 24 and returning all of your medication packagings. If you are scheduled for a telephone visit at 
Week 24, the maximum that you will be paid for full participation is $360.  The amount that you 
actually receive will be based upon the assessments that you complete and number of study 
medication packagings you return. You will also receive a baby gift of a box of 42 size 2 diapers 
and a tub of 40 baby wipes at the Week 10 or Week 24 visit (approximate value of $15.00 for 
both).  Please note that if you receive more than $600.00 compensation in one year for participation 
in research studies at the University of Pennsylvania, you must provide an Individual Tax Identification 
Number or Social Security Number for tax purposes. 
  
Will I have to pay for anything? 
There will be no cost to you for any of the study procedures. However, as part of this study you will 
receive and send text messages, and receive phone counseling. If you opt out of receiving a cell 
phone, standard text and voice messaging rates will apply as billed to you by your cell phone service 
provider.  
 
When is the study over?  Can I leave the study before it ends? 
This study is expected to end after all participants have completed all visits, and all information has 
been collected.  This study may also be stopped at any time without your consent because: 
• 
The Principal Investigator believes that it is necessary for your health or safety or that of your 
unborn baby.  Such an action would not require your consent, but you will be informed if such a 
decision is made and the reason for this decision. 
• 
You have not followed study instructions. 
• 
The National Cancer Institute (which is sponsoring the study), the study Principal Investigator, 
or the Food and Drug Administration (FDA) has decided to stop the study. 
If you decide to participate, you are free to leave the study at anytime.  Withdrawal will not interfere 
with your future care.   
 
Who can see or use my information?  How will my personal information be protected?   
We will do our best to ensure that the personal information that we collect on you and your baby will 
be kept private in your research record.  However, we cannot guarantee total privacy.  The personal 
information that we collect may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not be 
used.  The Food and Drug Administration (FDA) may review your research records.   
 
How will confidentiality be maintained and my privacy be protected?  
We will identify your research records only by a code number. The code number will not be based on 
any information that could be used to identify you (for example, social security number, initials, birth 
date, etc.). The master list linking names to code numbers will be kept separate from the research 
data. All research information will be kept in locked files at all times.  
The research team will make every effort to keep all the information you provide during the study 
strictly confidential, as required by law. The Institutional Review Board (IRB) at the University of 
Pennsylvania is responsible to protect the rights and welfare of research volunteers like you. The IRB 
has access to study information. Any documents you sign, where you can be identified by name, will 
be kept in a double-locked location. These documents will be kept confidential. All the documents will 
be destroyed when the study is over (though federal regulations require that this be done no less than 
three years after the study is formally closed).    
Upon completion of the study, the DNA blood sample will be kept in storage indefinitely to permit 
complete analysis of the sample.  However, the sample will forever be separated from your identity.  
There will be no way, not even through codes, to link the sample back to you.  These de-identified 
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samples may be shared with other researchers and used in other projects, but will not be identified as 
having come from you. 
If you choose to withdraw from the study after your DNA sample has been obtained, we will destroy all 
records in our research files connecting your identity with your sample(s). In this way, the samples 
could only be studied anonymously from this point forward.  
What information about me may be collected, used or shared with others?   
The following personal health information will be collected, used for research and may be disclosed or 
released during your involvement with this research study:  
• 
Name 
• 
Address 
• 
Telephone number 
• 
Email address 
• 
Social Security Number 
• 
Date of Birth 
• 
Photo Identification 
• 
Medical record number 
• 
Audio-recordings, if you agree to have your counseling sessions taped 
There is the possibility, if treatment is provided for study-related issues, that an electronic medical 
record (EMR) may be created for you. An Electronic Medical Record (EMR) is an electronic version of 
the record of your care within a health system. An EMR is simply a computerized version of a paper 
medical record.  
If you are receiving care or have received care within the University of Pennsylvania Health System 
(UPHS) (outpatient or inpatient), results of these research‐related procedures (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in your existing EMR maintained by UPHS.  
Once placed in your EMR, these results are accessible to appropriate UPHS workforce members that 
are not part of the research team. Information within your EMR may also be shared with others who 
are determined by UPHS to be appropriate to have access to your EMR (e.g., health insurance 
company, disability provider, etc).  
A description of this clinical trial will be available on http://ClinicalTrials.gov as required by U.S. Law. 
This web site will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this web site at any time. 
Why is my information being used? 
The research team will use your contact information to contact you during the study. Other information 
and the results of tests and procedures will be used to: 
• 
do the research 
• 
oversee the research 
• 
to see whether the research was done right 
Who may use and share information about me?   
The following individuals may use or share your information for this research study: 
• 
Dr. Kranzler and the study team at Penn that collects and reviews data for this study. The study 
team is located at two locations at the University of Pennsylvania in Philadelphia, PA 19104:  the 
Treatment Research Center, 3535 Market Street Suite 500 (Dr. Kranzler) and the Department of 
Obstetrics and Gynecology, 2000 Courtyard, Hospital of the University of Pennsylvania, 3400 Spruce 
St. (Dr. Srinivas). 
• 
Dr. Hand and the study team at Jefferson that collects and reviews data for the study. The 
study team is located at MATER 1233 Locust Street, 4th floor, Philadelphia, PA 19107. 
• 
Kevin Lynch, Ph.D. and staff from University of Pennsylvania’s Data Management Unit. 
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• 
The University of Pennsylvania Institutional Review Boards (The committees charged with 
overseeing research on human subjects) and the University of Pennsylvania Office of Regulatory 
Affairs 
• 
The University of Pennsylvania Office of Human Research (the office that monitors research 
studies) 
• 
Authorized individuals in the University of Pennsylvania School of Medicine who may monitor 
the research activities and findings, to protect the safety and welfare of all participants. 
Who, outside of the School of Medicine, might receive my information? 
The following individuals or organizations may receive your information from this research study:   
• 
The Office of Human Research Protections, which is the government agency that oversees 
research with humans 
• 
The University of Pennsylvania Institutional Review Boards (The committees charged with 
overseeing research on human subjects) and the University of Pennsylvania Office of Regulatory 
Affairs. 
• 
Philadelphia Department of Public Health Institutional Review Board 
• 
The Food and Drug Administration, which is the government agency that oversees the use of 
medications 
• 
The National Cancer Institute 
• 
Rachel Tyndale, Ph.D. University of Toronto, will analyze blood samples.  
• 
Brenda Curtis, Ph.D., MSPH 
• 
Greenphire ClinCard for processing study payments 
• 
StudyCue, LLC (operating as Sense Health) which is the web service that will provide text 
messaging services 
Once your personal health information is disclosed to others outside the School of Medicine, it may no 
longer be covered by federal privacy protection regulations.   
The Principal Investigator or study staff will inform you if there are any additions to the list above 
during your active participation in the trial. Any additions will be subject to University of Pennsylvania 
procedures developed to protect your privacy. 
FINANCIAL DISCLOSURE 
Dr. Schnoll, a co-investigator on this research study, has served as a consultant to Glaxo Smith Kline 
and Pfizer, companies that manufacture medications for nicotine dependence. Both companies are 
not involved with this study. If you would like more information, please ask the researchers  
or the study coordinator. 
How long may the School of Medicine use or disclose my personal health information?   
Your authorization for use of your personal health information for this specific study does not expire. 
Your information may be held in a research database.  However, the School of Medicine may not re-
use or re-disclose information collected in this study for a purpose other than this study unless: 
• 
You have given written authorization  
• 
The University of Pennsylvania’s Institutional Review Board grants permission 
• 
As permitted by law  
Can I change my mind about giving permission for use of my information? 
Yes, you may withdraw or take away your permission to use and disclose your health information at 
any time.  You can do this by sending written notice to the Principal Investigator of the study.  If you 
withdraw your permission, you will not be able to stay in this study. 
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What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study.   
You will be given a copy of this Research Subject HIPAA Authorization describing your confidentiality 
and privacy rights for this study.  
By signing this document you are permitting the School of Medicine to use and disclose personal 
health information collected about you and your baby for research purposes as described above. 
What happens if I am injured from being in the study?  
If you experience an emergency, please call 911 or go to your nearest emergency room.  If during the 
study, you have a medical problem that is not an emergency you may first contact the Principal 
Investigator: Dr. Kranzler (Penn) or Dr. Hand (Jefferson), whose numbers are listed on page one of 
this form. 
For participants at Penn: If it is after hours, and you cannot reach Dr. Kranzler, you will need to speak 
to the TRC study doctor on call. To do so, please dial the 24-Hour Emergency Beeper at (215) 505-
3799. The phone will ring once, and you will hear several beeps followed by no sound.  Then, dial 
your full phone number, including area code, and hang up the phone. The study doctor will receive 
your page and call you back at the number you entered.  If you are not contacted promptly, please try 
again.  The study doctor on call will evaluate the problem and, if needed, contact the obstetrics doctor 
on call. 
There are no plans for the University of Pennsylvania to pay you or give you other compensation for 
the injury.  You do not give up your legal rights by signing this form.   
If you think you have been injured as a result of taking part in this research study, tell the person in 
charge of the research study as soon as possible.  The researcher’s name and phone number are 
listed on the first page of this consent form. 
Who can I call with questions, complaints or if I’m concerned about my rights as a research 
subject? 
If you have questions, concerns or complaints regarding your participation in this research study or if 
you have any questions about your rights as a research subject, you should speak with the Principal 
Investigator listed on page one of this form.  If a member of the research team cannot be reached or 
you want to talk to someone other than those working on the study, you may contact the Office of 
Regulatory Affairs with any question, concerns or complaints at the University of Pennsylvania by 
calling (215) 898-2614. 
For more information about the Jefferson Institutional Review Board or Jefferson’s Human Research 
Protection Program, please visit their website at 
http://www.jefferson.edu/human_research/irb/index.cfm, or for questions about your rights as a 
research participant at Jefferson: Thomas Jefferson University, 1015 Chestnut St. Suite 1100 
Philadelphia PA 19107; Phone (215)–503-8966. 
 
When you sign this form, you are agreeing to take part in this research study. This means that 
you have read the consent form, your questions have been answered, and you have decided to 
volunteer.  Your signature also means that you are permitting the University of Pennsylvania to 
use your personal health information collected about you for research purposes within our 
institution. You are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of this study. 
 
A copy of this consent form will be given to you.  
 
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Agreeing to receive a cell phone is not a requirement to participate in the study.  Please initial your 
decision: 
 
Yes, I agree to receive a cell phone: __________ 
 
No, I do not agree to receive a cell phone: ______ 
 
 
 
 
Agreeing to audio recording is not a requirement to participate in the study.  Please initial your 
decision: 
 
Yes, you agree that we can record your counseling sessions:   __________ 
 
No, you do not agree that we can record your counseling sessions:   ________ 
 
 
______________________       ____________________________________ 
Name of Subject (Please Print)  
Signature of Subject   
           Date 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining Signature                                  
 
Date 
Consent (Please Print) 
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