Placebo-controlled Trial of Bupropion for Smoking Cessation in Pregnant Women

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.

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.

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 multiple gestations

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 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 smoking cessation treatment other than psychoeducational interventions

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.