Clinical trial NCT01744574
Conditions: Tobacco Cessation
Sponsor: University of Minnesota
Start date: 2012-12-01; Completion date: 2017-07-27
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Data suggest that progesterone may improve smoking cessation outcomes perhaps by reducing impulsive behavior. However, the clinical literature on this topic is lacking. Therefore, in Project I we are proposing a double-blind randomized controlled trial to assess the role of exogenous progesterone on impulsivity and smoking cessation in a sample of males and females who are motivated to quit smoking.

Detailed description:
Subjects will be stratified by sex and then randomly assigned to active progesterone (PRO) or placebo (PBO).

Telephone screening and visit invitation leads to the consent process and in-person screening including medical-psychiatric evaluation for inclusion/exclusion, then randomization and medication induction, stable medication with medication reduction and final evaluation for secondary outcomes.

Arms: arm 1: Placebo - subjects will take 200 mg twice daily, orally (approximately 8am and 8pm) for twelve weeks starting seven days prior to the assigned quit date. They will also receive smoking cessation behavioral counseling. arm 2: The progesterone will be given in the form of an active micronized natural progesterone (Prometrium). All subjects will take 200 mg twice daily, orally (approximately 8am and 8pm) for twelve weeks starting seven days prior to the assigned quit date. They will also receive smoking cessation behavioral counseling.
Interventions: intervention 1: Placebo intervention 2: Progesterone intervention 3: Smoking Cessation Behavioral Counseling
Intervention descriptions: intervention 1: Placebo - subjects will take 200 mg twice daily orally (approximately 8am and 8pm) for twelve weeks starting seven days prior to the assigned quit date. intervention 2: The progesterone will be given in the form of an active micronized natural progesterone (Prometrium). All subjects will take 200 mg twice daily orally (approximately 8am and 8pm) for twelve weeks starting seven days prior to the assigned quit date. intervention 3: Subjects will receive weekly smoking cessation behavioral counseling.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 28 
SCOR Grant: 
Project I 
 
Sex Differences and Progesterone:   
Association with Impulsivity and Smoking Cessation 
 
“Hormones & Smoking Cessation” 
 
Principal Investigator: 
Sharon S. Allen, M.D., Ph.D. 
 
 
 
 
 
 
 
Study Protocol 
 
 
 
Version: 
14.0 
 
 
Date: 
January 24, 2017 
 


Page 2 of 28 
A.  SPECIFIC AIMS  
Cigarette smoking persists as the leading cause of preventable morbidity and mortality (Centers for Disease 
Control and Prevention (CDC), 2010). Although there have been many advancements in smoking cessation 
interventions, the majority of smokers relapse soon after a quit attempt (CDC, 2010; Benowitz, 2009). Despite 
being more likely to develop a smoking-related disease, females are at a higher risk for smoking relapse 
compared to males (U.S. Department of Health and Human Services (USDHHS), 2001; Perkins & Scott, 
2008). While the specific causal mechanisms associated with the sex difference in relapse rates remain 
unknown, increasing evidence suggests sex hormones may drive this disparity.  
Overall, research to date indicates that estrogen is associated with the facilitation of drug-abuse behaviors, 
whereas progesterone is associated with reduction of these behaviors (Carroll & Anker, 2010; Lynch & 
Sofuoglu, 2010).  While the clinical literature is mixed, our work offers additional support for this theory as the 
luteal phase (high progesterone) of the female menstrual cycle appears to be associated with decreased 
smoking-related symptomatology (Allen et al 2009b) and improved smoking cessation outcomes (Allen et al 
2008; Allen et al 2009c) relative to the follicular phase (low progesterone).   
Cigarette smokers appear to be more impulsive than non-smokers (Bickel et al 1999), and higher levels of 
impulsivity are associated with increased risk for smoking relapse (Doran et al 2004).  Sex differences have 
been observed in this association such that females are more susceptible to the effects of impulsivity on 
smoking (Nieva et al 2011).  Preliminary evidence suggests sex hormones may play a role as females who 
have recently quit smoking have less impulsive behavior while in the luteal phase than in the follicular phase 
(Allen et al 2009a). Further, within the animal literature, delivery of exogenous progesterone has been shown 
to decrease impulsive behavior (Llaneza & Frye, 2009). 
Taken together, these data suggest that progesterone may improve smoking cessation outcomes perhaps by 
reducing impulsive behavior.  However, the clinical literature on this topic is lacking. Therefore, in Project I we 
are proposing a double-blind randomized controlled trial to assess the role of exogenous progesterone on 
impulsivity and smoking cessation in a sample of males and females who are motivated to quit smoking.  
Subjects (n=200) will be stratified by sex and then randomly assigned to active progesterone (PRO; n=50 
males and 50 females) or placebo (PBO; n=50 males and 50 females) to address the following specific aim:   
Aim 1: Investigate sex differences in the effect of exogenous PRO compared to placebo on impulsivity 
and smoking cessation  
Hypothesis 1: For both males and females, a lower proportion of subjects randomized to PRO will 
relapse by 4 weeks after quit date compared to those randomized to PBO. 
Hypothesis 2: For both males and females, subjects randomized to PRO will have more days to relapse 
compared to those randomized to PBO. 
Hypothesis 3: There will be a sex difference in smoking relapse such that females, regardless of 
randomization assignment, will have fewer days to relapse compared to males. 
Hypothesis 4: Impulsivity will be a stronger relapse predictor in females than males.  
Hypothesis 5: Among those with higher levels of serum PRO the influence of impulsivity on smoking 
relapse will be dampened. 
Given that less than three percent of those who attempt to quit smoking remain abstinent six months later 
(Benowitz, 2009), there is an urgent need to gain a better understanding of the dynamic process involved in 
smoking cessation. This project will provide new knowledge regarding the possible protective role of 
progesterone against smoking relapse in males and females.  
 
 
 
 
 


Page 3 of 28 
B. RESEARCH STRATEGY  
 
B.1. SIGNIFICANCE  
Cigarette smoking continues to be the number one cause of preventable morbidity and mortality in the United 
States (CDC, 2010). Compared to males, females are at an increased risk for development and maintenance 
of nicotine addiction (USDHHS, 2001). Preclinical and clinical studies have offered evidence to explain these 
observed sex differences, suggesting that sex hormones may modulate the reward system and related nicotine 
response (Lynch & Sofuoglu, 2010). Specifically, high levels of estrogen are associated with a heightened 
response to nicotine; whereas, high levels of progesterone are associated with a blunted response (Carroll & 
Anker, 2010; Lynch & Sofuoglu, 2010). Further, within the animal literature the administration of progesterone 
has been shown to be associated with reduced reinforcing effects of drugs, as well as a decrease in self-
administration and drug-seeking behavior (Carroll & Anker, 2010).  
Recent studies suggest that progesterone may play a key role in the observed sex differences in addictive 
behaviors. A review by Lynch & Sofuoglu (2010) concluded that progesterone (PRO) may counter the 
enhanced vulnerability in females by altering the biological response to nicotine’s reinforcing effects. Other 
clinical research on smoking cessation by menstrual phase has indicated that the follicular phase (low PRO) 
may be associated with more favorable outcomes when paired with nicotine replacement therapy (Franklin et 
al 2007; Carpenter et al 2008); whereas the luteal phase (high PRO) may be associated with more favorable 
outcomes when either no medication or non-nicotine medications (i.e. bupropion) are used (Allen et al 2008; 
Mazure et al 2011). However, the specific mechanisms as to how PRO may assist with smoking cessation 
efforts remain unknown. Given that PRO has been shown to reduce impulsive behaviors in animals (Llaneza 
and Frye, 2009) one theory is that PRO blunts impulsivity in humans and, therefore, protects against smoking 
relapse. 
Further clinical research has focused on association of various personality traits, primarily impulsivity. 
Impulsivity has four factors including a lack of premeditation regarding the consequences of behavior, lack of 
perseverance when tasks are boring or aversive, sensation seeking and urgency, and the tendency to behave 
impulsively while experiencing negative affect (Doran et al 2009). Sex differences in the association between 
impulsivity and smoking behavior have been observed. For example, one recent study observed that high 
levels of impulsivity were associated with increased nicotine use in females, but not males (Stoltenberg et al 
2008). A second study observed a positive association between two factors of impulsivity – sensation seeking 
and general activity – and number of cigarettes smoked per day in females, but not males (Nieva et al 2011). 
The role of sex hormones in these associations is unclear; however, taken together this offers evidence for a 
possible interaction between PRO, impulsivity and smoking behavior.  
This SCOR application proposes robust comparisons of hormonal influences in clinical and preclinical studies. 
Here, in Project I, we propose direct and additive conditions. Specifically, we will assess the effects of PRO, 
compared to placebo (PBO), as well as the sex differences on impulsivity and smoking cessation outcomes in 
females and males who are motivated to quit smoking using a 12-week double-blind randomized clinical trial.  
This project, especially in the context of the other projects, is highly significant in several domains. First, the 
proposed work directly compares female and male subjects with respect to PRO modulation of smoking 
cessation. Second, because PRO and impulsivity both have a role in smoking cessation and relapse, a direct 
comparison of PRO versus PBO on impulsivity is important. Third, these data will directly address (a) the role 
of PRO on smoking cessation outcomes, (b) the role of sex differences on smoking cessation outcomes, (c) 
the role of impulsivity on smoking cessation outcomes, and (d) interactions of sex, PRO and impulsivity on 
smoking cessation outcomes. Fourth, while Project I will focus solely on nicotine and PRO effects on nicotine, 
Project II, using similar design features, will focus on cocaine with co-morbid nicotine use in humans and the 
combined effects of PRO and atomoxetine. Project III will conduct parallel preclinical studies to both projects. 
Therefore, the complete data set will provide unique and significant insights into sex differences as well as, 
translational data. Finally, the combined expertise of the assembled named investigators is unique and greatly 
enhances the probability that the work will be completed as proposed and that significant findings will be 
forthcoming.  
 


Page 4 of 28 
 
B.2. PRELIMINARY STUDIES  
B.2.1. Impulsivity Varies by Menstrual Phase after Exposure to Nicotine. Goal: This cross-over study 
aimed to measure differences in nicotine response between follicular (F) and luteal (L) menstrual phases in a 
sample (n=20) of female smokers between 
the ages of 18 and 40. Results: After 
exposure to nicotine nasal spray, subjects in 
the F phase became significantly more 
impulsive on the Immediate Memory Task 
computer program (Doughtery et al 2002) 
compared to subjects in the L phase (Figure 
1). Relevance: Sex hormones appear to 
impact the level of impulsivity, such that high 
levels of progesterone are associated with 
less impulsivity after exposure to nicotine. The 
association 
between 
progesterone 
and 
impulsivity may be associated with risk for 
relapse.  
B.2.2: Smoking Satisfaction & Enjoyment Vary by Menstrual Phase during Ad Libitum Smoking. Goal: 
The purpose of this cross-sectional study was to investigate the differences in reinforcing effects (mCEQ) 24 of 
smoking by menstrual phase and depressive symptoms in a sample of female subjects (n=39) who were 
classified into four groups: no depressive symptoms follicular phase (NDS-F), no depressive symptoms luteal 
phase (NDS-L), depressive symptoms follicular 
phase (DS-F) and depressive symptoms luteal 
phase (DS-L). Results: Smoking Satisfaction 
varied by menstrual phase in the NDS group but 
not the SDS group (F-NDS: 5.2±0.5; L-NDS: 
3.4±0.5; 
F-SDS: 
4.5±0.4; 
L-SDS: 
4.8±0.3; 
p=0.016; Figure 2) and a similar trend was 
observed within the Enjoyment subscale (F-NDS: 
4.4±0.6; L-NDS: 1.7±0.6; F-SDS: 3.6±0.5; L-SDS: 
2.9±0.5; p=0.089). Relevance: Among those 
without depressive symptoms, sex hormones 
appear to impact the level of reinforcing effects of 
smoking, such that high levels of progesterone 
are associated with less smoking satisfaction and 
less enjoyment.  
B.2.3. Pharmacokinetics of Nicotine varies by Menstrual Phase in Women without Depressive 
Symptoms. Goal: This cross-over study 
aimed 
to 
measure 
menstrual 
phase 
differences 
in 
pharmacokinetics 
after 
exposure to nicotine nasal spray within a 
sample of abstinent female smokers with 
regular menstrual cycles who either had 
depressive symptoms (n=23) or did not 
(n=24). Results: There was a significant 
interaction between depressive symptoms 
status and menstrual phase such that those 
without 
depressive 
symptoms 
had 
a 
significant menstrual phase difference in their 
maximum 
nicotine 
concentration 
levels 
(p=0.020; Figure 3). Relevance: In women 
without 
depressive 
symptoms 
high 


Page 5 of 28 
progesterone levels are associated with lower nicotine response; this may be associated with risk for relapse.  
B.2.4. Changes in Estradiol/Progesterone (E2/P) Ratio are Associated with Changes in Craving. Goal: 
This cross-over study aimed to assess the influence of the E2/P ratio on smoking-related symptoms of 
withdrawal (MNWS), smoking urges (Brief-QSU), and reinforcing effects of smoking (mCEQ) using a within 
subject analysis in a sample of female smokers (n=50) with regular menstrual cycles between the ages of 18 
and 40. Results: During ad libitum smoking, an increase in the E2/P ratio was associated with an increase in 
craving on two independent items of measurement: mCEQ (t=2.38, p=0.02) and MNWS (t=1.92, p=0.06). 
Relevance: Changes in sex hormone levels are associated with changes in craving for cigarettes.  
 
B.3. INNOVATION 
This project offers the following two highly innovative features. First, directly comparing PRO effects on 
impulsivity, as well as smoking cessation and relapse in females and males is highly innovative. Second, 
chronic use of PRO as a smoking cessation aid has not yet been investigated. Overall, the high level of 
innovation stems from (a) reliance on previously obtained data from human and animal studies by the 
experienced study team, (b) the translational strategies of furthering direct comparisons in the proposed clinical 
and preclinical research, (c) combining extant data to address a unique series of questions regarding 
determinants and modulators of drug cessation, and (d) use of rigorous multidisciplinary methods (such as 
thorough neurocognitive assessment of impulsivity, and detailed hormone and menstrual cycle measurement) 
to implement the projects and answer the questions posed.  
 
B.4. APPROACH 
The two clinical projects - Projects I (Allen) and II (Specker) - will use parallel methods and measures, 
deviating only as appropriate for the differences in the populations. The details are described below. 
 
B.4.1. Study Design 
This double-blind, clinical trial (Figure 4) will prescreen an estimated 600 potential subjects, consent and 
evaluate approximately 300 potential subjects and ultimately enroll 250 subjects to ensure 200 subjects 
provide a primary relapse outcome measure at four weeks after quit date. Subjects will be stratified by sex then 
randomized to one of two groups (n=100 per group / 50% female): Progesterone (PRO) or Placebo (PBO). 
Telephone 
screening 
and 
visit 
invitation (20 minutes) leads to the 
consent 
process 
and 
in-person 
screening 
including 
medical-
psychiatric 
evaluation 
for 
inclusion/exclusion (two visits, two 
hours each), then randomization and 
medication induction (seven days), 
stable medication (70 days) with 
medication 
reduction 
and 
final 
evaluation for secondary outcomes 
(over the last seven days). These 
procedures will be conducted as 
described below. 
 
B.4.2. Setting, Recruitment, Subjects 
Setting: This project will be conducted at the Delaware Clinical Research Unit (DCRU). The DCRU has both 
inpatient and outpatient resources for the spectrum of biomedical research including special capabilities that 
were developed for study of substance use disorders. The Clinical and Translational Sciences Institute (CTSI), 
runs the DCRU and functions parallel and support the activities of the NIH funded CTSA, which it predated. 


Page 6 of 28 
The DCRU includes: reception area, examination rooms, meeting rooms, clinical interview rooms, testing 
rooms for computer based performance tasks, a wet lab for handling bloods and other specimens, freezers (to 
-80°C), all essential staff offices, each with multiple telephone and computer lines through the University of 
Minnesota servers, a locked limited access protocol, equipment and medication rooms, as well as secure 
cabinets for study files and essential supply and support areas and services. 
Recruitment: To meet recruitment goals, we aim to enroll a total of 250 subjects (~6 subjects/month) to ensure 
a final sample size of 100 females and 100 males. Our primary recruitment method will be advertising in the 
mainstream media. While this type of recruitment can be challenging, our team has been successful with this 
form of recruitment. For example, our current study recruiting females between the ages of 18-40 has had 
success with Facebook advertising. Specifically, over the past seven months we have advertised on Facebook 
resulting in 6,483 clicks to our website, an estimated 180 phone calls to our clinic and an enrollment of 29 
subjects (~4 subjects/month). We regularly use television, radio, mailings, and other internet sources to identify 
study subjects with similar success.  Using all of these methods, we have successfully enrolled ~8 
subjects/month over the past year in our two ongoing tobacco use research studies. 
Subjects and Eligibility: Females 18-50 years of age with regular menstrual cycles and males, 18-60 years of 
age, (n=300; 50% females) will be enrolled who are current smokers and are motivated to quit smoking.  
Inclusion Criteria: • Male 18 to 60 years old or female between 18 and 50 years old; •Self-report smoking ≥ 5 
cigarettes/day for at least the past year; • Motivated to quit smoking (self-report ≥ 7 on 10-point Likert-type 
scale); • In stable physical/mental health; • Self report of regular menstrual cycles (female only) • Willing to use 
double-barrier contraception method if sexually active and not surgically sterilized; • English fluency; • 
Understand the study procedures and able to provide informed consent; •Ability to participate fully in research 
elements for the duration of the trial. 
Exclusion criteria: • Current use of other types of tobacco, nicotine replacement therapy, or smoking cessation 
medications; • Current or recent (< 3 months) breastfeeding (females only), • Current or planned pregnancy 
within the next three months (females only); • DSM-IV diagnoses for psychotic disorders, bipolar disorder, 
ADHD, major depressive disorder within the last 3 months, • Substance dependence within the last 3 months 
with the exceptions of nicotine dependence and non-daily use of marijuana.; •Unstable psychotropic 
medications (< 3 months); • Current use of exogenous hormones, finasteroid (propecia), efavirenz, red clover, 
ketoconazole and other drugs that are CYP3A4 inhibitors; •Conditions contraindicated to progesterone 
treatment (including, but not limited to, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or 
bleeding disorders, heart disease, diabetes, history of stroke, allergy to peanuts, hypersensitive to 
progesterone and liver dysfunction). 
 
B.4.3. Visit Sequence & Procedures  
Screening Visits (Visits 1 and 2): Initial screening procedures for Project I and II will be identical except for drug 
use related criteria, testing and evaluation. Candidates completing the consent process will be screened in a 
two-visit process. For males, this two-visit process will be scheduled within two weeks of completion of the 
phone interview. For females, this two-visit process will be completed during the follicular phase of their 
menstrual cycle to avoid any potential menstrual phase effects on smoking behavior or mood measures, as 
well as to limit wait time for initial study procedures (details below). Therefore, after the phone screen females 
will be told to call with the first day of their next period, and then the two-part screening visits will be scheduled 
during days 1-7 (where Day 1 is the onset of menses) of the menstrual cycle. We have used this procedure 
with success in our ongoing trial on menstrual phase and depressive symptoms.  
At the first of two screening visits (Screening Visit 1), the study will be described in detail to candidates by the 
study coordinator, and informed consent will be obtained. Subjects agreeing to participate will undergo 
medical, psychiatric and other evaluation to determine eligibility. The medical evaluation will include: brief 
physical exam (height, weight, blood pressure, heart rate, and medical history interview), audiotaped 
psychiatric interview, carbon monoxide level and a blood draw (for measurement of serum hormone levels and 
liver function via ALT and AST measurement) and a urine pregnancy test (females only). Trained staff will 
conduct all interviews including the Structured Clinical Interview for DSM-IV (SCID; First, 1995) and instrument 
administration with audiotapes reviewed regularly to sustain fidelity. Self-report instruments measuring 


Page 7 of 28 
impulsivity, personality characteristics, stress, caffeine use, smoking withdrawal and behavior will be 
completed. At the second screening visit (Screening Visit 2; scheduled within three days of the first screening 
visit), baseline impulsivity tasks will be completed. Females will then be provided with urine luteinizing hormone 
(LH) testing kits with instructions for daily use. The quit date will be set based on LH testing results (details 
below). The investigators will review the data to determine eligibility. Subjects meeting eligibility criteria will be 
given instructions on when to come back for their Baseline Visit (details below). 
Quit Date Assignment: This procedure will be identical to Project II and is described in detail here (Table 1). 
For female subjects the quit date will be assigned during the luteal phase. We have selected the luteal phase 
(typically the last 14 days of the menstrual cycle; Yee et al 1999) for quit date given that our prior work has 
demonstrated that this menstrual phase is associated with improved smoking cessation outcomes (Allen et al 
2008). Therefore, using identical techniques from our prior work (Allen et al 2008) the quit date will be set as 
follows: First, to determine date of ovulation, female subjects will use LH tests. Several studies by our group 
and others have shown that ovulation can accurately be predicted by urine LH testing (e.g. Allen et al 1999, 
Allen et al 2000, Allen et al 2008, Grinsted et al 1989, Luciano et al 1990). Using the First Response urine 
testing kit (Carter Products), subjects will determine their LH peak with daily urine testing during specific days 
of the cycle (See Appendix A for instructions). The testing will be done for ten consecutive days starting on Day 
8-12 (depending on cycle length). Although the surge may last up to three days, the first day of the surge is 
most 
important, 
because 
it 
predicts 
ovulation 24-48 hours later. In our prior 
studies, as well as our current study, 
subjects found the test easy to use and 
have been compliant. If no LH surge is 
identified in the first two months, that female 
subject will be labeled anovulatory and 
dropped for ineligibility (estimated < 5% 
occurrence). Second, once ovulation is 
detected, the baseline appointment and quit 
date will be scheduled. The baseline 
appointment will occur within three days of 
ovulation. Quit date will be set for seven 
days after the baseline appointment (i.e. 
seven to ten days after ovulation).   
Since this entails a delay of variable 
duration from Screening Visit 2 to Baseline 
Visit (thus impacting timing of medication initiation) across female subjects, each male subject will be matched 
to a female subject for a similar delay so that, across the male and female groups, study procedures will be 
follow a similar chronology. 
Baseline Visit (Visit 3): When the LH surge occurs female subjects will be instructed to come into the clinic 
within three days for their baseline visit and to start medication. Male subjects will be instructed to come into 
the clinic according to their assigned delay (per list generated by the Biostatistics Core). This visit will occur 
seven days prior to quit date. At this visit, subjects will be randomized to PRO or PBO within strata defined by 
sex. The Statistical Analysis Core (SAC) will generate the randomization tables (one for each sex), and the 
Clinical Trials Research Pharmacy will use it to determine randomization assignment. Randomization 
assignment will be stored in a secure file in a secure location at the Clinical Trials Research Pharmacy, to be 
shared only with the SAC. All other project staff including PI and study coordinator, as well as the participant, 
will remain blinded to the randomization assignment.  
At the baseline visit subjects will provide a blood sample (for hormone assessment), breath sample (to confirm 
smoking status via carbon monoxide breathalyzer), have their vital signs (blood pressure, heart rate, weight) 
measured, be informed of their quit date, and receive brief behavioral counseling to prepare for their quit date. 
At the end of this visit subjects will be paid for their time and given study medication along with instructions for 
taking the medication (beginning at 8PM that day), as well as a clinic visit schedule for the remaining clinic 
visits. This visit will take approximately one hour to complete. 


Page 8 of 28 
Weeks 0-12 (Visits 4-16): The Week 0 clinic visit will occur on the assigned quit date. Subjects will attend clinic 
visits on a weekly basis thereafter for twelve weeks. At weeks 0-4, week 8 and week 12 blood samples 
(hormone measurement) will be collected. Urine samples will be collected at all visits from all participants 
(pregnancy tests for females; and visual inspection of urine color to confirm compliance with taking study 
medication via riboflavin filler). At weeks 0-4, week 8 and week 12 urine will be saved for biochemical 
confirmation of smoking status via nicotine/cotinine levels. Subjects will also complete several forms and 
questionnaires (described below). Subjects will also return the medication bottle and unused medication, be 
given a new two-week supply and adverse events will be assessed. At Week 11, study medication will be 
discontinued. Finally, subjects will receive brief smoking cessation behavioral counseling (Appendix A). At the 
end of each visit subjects will be paid for their time. These visits will take approximately 30-45 minutes to 
complete.  
Study Adherence: To encourage compliance the following will occur: (1) at the Baseline Visit, subjects will be 
given a schedule of all remaining appointments; (2) at each visit the subjects will be given an appointment 
reminder card for the next visit; (3) reminder calls, texts and/or emails (per subject’s preference) will be placed 
or sent the day before each visit; (4) subjects will be routinely reminded that regardless of their smoking status 
their data are valuable and important; and (5) regardless of smoking status, subjects will be compensated at 
each visit (described in the following). If a subject misses a visit, study staff will try to reach him/her by phone 
that day to reschedule for one to three days later. If that does not work, staff will contact the subject’s 
designated ‘contact person’ (i.e., someone who does not live with the subject but knows how to get in touch). If 
a subject does not attend any visits after the screening visits, he/she will be labeled as a “drop” and replaced. If 
the subject discontinues from the study after randomization but before the final follow-up visit, he/she will be 
labeled an “incomplete” but not replaced. If a subject does not quit on their assigned quit date or relapses later, 
she/he will be encouraged to stay in the study and make another quit attempt; such that we will follow them for 
three months regardless of smoking status. Subjects who complete the four week follow-up period after quit 
date, regardless of smoking status, will be labeled a “completer” for the primary outcome and not replaced. Our 
sample size goal to sufficiently power the primary outcome is for 200 completers. 
 
B.4.4. Subject Compensation 
Subjects will receive compensation at each study visit for their time and effort. Subjects will be compensated 
$25 for Screening Visit 1 and $25 for Screening Visit 2.  For each visit thereafter, they will be compensated $10 
for their time and completing study procedures plus $10 to cover transportation costs (Total=$20). The subject 
will also be eligible for study bonuses: $100 for missing fewer than three follow-up clinic visits and a $30 bonus 
for attending the Week 4, 8 and 12 clinic visits.  At Screening Visit 2, Week 4, Week 8, and Week 12 subjects 
will also be compensated for their performance on the BART computer task.  The amount of compensation 
depends on their performance.  It is estimated that subjects will receive between $10 and $50 each time they 
complete the task (average estimated payment=$35 each time). Therefore, subjects will receive approximately 
$660 ($25 Screening Visits x 2 visits + $20 follow-up visits x 14 visits + $190 in bonus payments + an average 
of $140 in BART payments).  
 
B.4.5. Study Medication  
Subjects will be stratified by sex and then randomly assigned to PRO or PBO, as described above.  All 
medication (active and placebo) will be prepared by the University of Minnesota Clinical Trials Research 
Pharmacy, which is a specialized facility that prepares medication clinical trials including our ongoing research. 
The research pharmacist (D Luke Pharm D) will provide medications. There is oversight and monitoring with 
regular audits by local regulatory boards including the IRB. This study requires double-blind procedures, 
therefore progesterone will be over encapsulated and be identical to the placebo capsules. To prevent against 
the possibility of missed medication in the event of a missed clinic visits, subjects will receive a two week 
supply (to ensure no medication is missed in the event of an unexpected miss clinic visit due to illness or 
transportation issues, for example) of study medication from study staff at each clinic visit beginning with the 
Baseline Visit. Medications will be discontinued at the Week 11 clinic visit. 


Page 9 of 28 
Progesterone: 
The 
progesterone will be 
given in the form of 
an active or placebo 
micronized 
natural 
progesterone (generic 
Prometrium). 
All 
subjects will take 200 
mg 
twice 
daily 
(approximately 
8am 
and 8pm) for twelve 
weeks starting seven 
days 
prior 
to 
the 
assigned quit date. 
The 
dosage 
was 
selected 
to 
ensure 
that 
serum 
progesterone 
levels 
will be consistent with 
those observed in the 
natural Luteal phase 
of the menstrual cycle 
(6-14 ng/mL) since that phase has been shown to be favorable for smoking cessation (Allen et al 2008). We 
expect the following serum progesterone levels by group (Figure 5): (1) females + PRO 9-13 ng/mL; (2) males 
+ PRO 6-7 ng/mL; (3) females + PBO, varies by menstrual phase from 1-14 ng/mL; and (4) males + PBO 0-1 
ng/mL (Goletiani et al 2007; Reed et al 2010; Yen et al 1999). Delivery of exogenous progesterone has been 
successfully used in prior research with a shorter duration of use (i.e. < 1 month) and is generally well tolerated 
(Sofouglu et al 2001; Sofouglu, et al 2004; Goletaini et al 2007; Reed et al 2010). The most common adverse 
effect in males and females is sedation. Less common effects include breakthrough bleeding (females), 
nausea (females and males) and breast tenderness (females) (de Lignieres, 1999; Goletaini et al 2007). While 
it is possible that progestins may contribute to risk for thromboembolism, we will be using natural micronized 
progesterone instead of synthetic progestins. Natural micronized progesterone is not known to be associated 
with thromboembolic risk (PDR, 2002; Goletaini et al 2007), and consequently is a safer choice. Micronized 
progesterone is not a form of birth control. Therefore, all female subjects will be educated on the importance of 
using a double-barrier method to protect against pregnancy.  
Adverse Effects: If a subject is unable to tolerate these side effects of the study medication, those subjects will 
have the dosage decreased to 200 mg daily. The blind will not be broken to make this determination. Dr. Allen 
will assess the adverse event based on subject self-report of symptoms and advise a dose reduction if needed.  
 
B.4.6. Study Measures 
Prevalence of Relapse (Primary Outcome) and Days to Relapse (Secondary Outcomes): We will assess 
smoking status using three methods (one based on self-report and two based on biochemical confirmations). 
First, at each clinic visit the TimeLine FollowBack (TLFB) method will be completed. The TLFB is a validated 
retrospective data capture technique (Sobell et al 1996). Marijuana users will complete an additional TLFB for 
marijuana use. Second, the first biochemical confirmation is expired air carbon monoxide (CO) measurement. 
The CO levels will be collected to each visit. Expired air CO sensitivity and specificity is approximately 90% 
(Jarvis et al 1987). Subjects will exhale into a CO monitoring device (Bedfont Scientific Limited Company), 
calibrated weekly to verify accuracy. For sample collection, subjects blow into a breathalyzer and analysis 
occurs immediately. CO levels > 5 ppm are indicative of acute smoking. Third, we will measure urinary 
cotinine, a major metabolite of nicotine and a biological indicator of nicotine exposure. A spot urine sample will 
be collected at the Week 4 and Week 12 clinic visits. The cotinine test has a sensitivity of 96-97% and a 
specificity of 90-100% (Jarvis et al 1987). A cotinine level of less than 15 ng/mL is indicative of abstinence 
(half-life of cotinine is 19-30 hours). Samples will be analyzed in batches at the Minneapolis Medical Research 


Page 10 of 28 
Foundation Division of Toxicology using gas chromatography (Hewlett-Packard) in Year 5. The use of two 
different forms of biochemical confirmation of smoking status will eliminate potential false-positives that occur 
with using only one of these items.  
Days to relapse will be defined using continuous abstinence (CA), prolonged abstinence (PA) and point 
prevalence (PP) definitions (Hughes et al 2003). CA, a traditional measure, defines a single puff off a cigarette 
as relapse. The more liberal PA measure reflects sustained abstinence and defines relapse as seven 
consecutive slips (i.e., a puff or more) without a 24-hour period between any slip. The day of relapse is the first 
day of a slip. The CA and PA smoking outcomes will ranging from 0 (i.e. smoking on quit date) to 90 (i.e. not 
smoking at the end of the study). PP is a binary outcome of smoking relapse and is defined as a single puff off 
a cigarette during the seven days prior to a pre-specified time point of interest – Week 4 and Week 12. Week 4 
prevalence of relapse is our primary outcome; week 12 prevalence of relapse is a secondary outcome. Self-
report and biochemical measures will be combined to determine CA, PA, and PP. 
Impulsivity Measures (Secondary Outcome): This P50 will examine “impulsivity” correlates broadly in rodents 
and humans across two substance use disorders (nicotine, cocaine-nicotine). Here we operationalize 
determination of impulsivity with several instruments.  
Subjects will complete three self-report measures that have been computerized at each clinic visit beginning at 
Screening Visit 2. These measures will assess the characteristics of impulsivity, inhibition, planfulness, and 
cognitive impairments, key areas of focus in this grant.  
 Behavioral Inhibition/Activation scales (BIS/BAS): These short 20 items forms commonly used scales to 
study externalizing tendencies (Carver and White, 1994). Investigators in Project II have used this 
instrument with success.  
 Barratt Impulsiveness Scale (BIS): This item contains 30 item self-report measure self-control (Patton et 
al 1995). Doran and colleagues (2004) demonstrated that impulsivity, as measured with this item, was a 
predictor of smoking relapse.  
 Brief Self Control Scale (BSCS): This item consists of 13 questions rated on a 4-point scale from “very 
true” to “very false” on items reflecting the ability to control problematic behaviors (Tangney et al 2004).  
The Impulsivity Tasks represent two forms of impulsivity, 1) impaired cognitive inhibitory mechanisms, and 2) 
deficits in motor inhibitory mechanisms. “Delay discounting” entails higher-level cognitive inhibitory processes 
that may characterize the behavior of individuals who are drug dependent (Bickel and Marsch, 2001) tobacco 
users (Baker et al. 2003), cocaine users (Monterosso et al, 2001), other drug users (e.g. Vuchinich and 
Simpson, 1998; Kollins, 2003) and pathological gamblers (Dixon et al, 2003).   The following items will be 
completed at Screening Visit 2, Week 4, Week 8 and Week 12: 
 Delay Discounting Task: Developed by de Wit and colleagues (Richards et al, 1999), delay discounting 
refers to the reduction in value of a reward over time relative to its immediate worth. One’s discount rate, 
also known as a time preference, is a measurable individual difference and involves a series of choices 
(e.g. Petry and Casarella, 1999): one option is an immediate payment (e.g. $1); the second option is a 
larger payment (e.g. $50) after a delay (e.g. 6 hours to 25 years). Titrating the payment amounts at each 
delay interval allows the identification of points of indifference (the point at which the subject switches 
from choosing the immediate to the larger reward at a given delay interval). We additionally included a 
probability discounting condition to measure risk aversion in addition to time preference (Richards et al, 
1999). 
 GoStop Task: This task measures response inhibition.  A series of five-digit numbers are presented on a 
computer monitor at a rate of 500ms for ever two seconds. Subjects are instructed to click the mouse 
button when the number they see is identical to the previous number. Half of the numbers change color 
from black to red at 50, 150, 250 and 350. Subjects are instructed to respond to the matching number 
only when the displayed number is black. The primary outcome of this task is the percent of inhibition 
failures for the 150ms delay (Dougherty et al 2008). This item has been successfully used to assess 
tobacco dependence and smoking behavior (Billieux et al 2010). 
 Balloon Analogue Risk Task (BART): This task, with 15 replications/session, is a measure of risk-taking. 
It involves displaying a small balloon on a computer screen. Each “pump” to inflate the balloon 
accumulates five cents, with each pump potentially breaking the balloon. The average pumps to the 


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breaking point is 64. To ensure attentive responding, subjects will receive the actual amount of money 
accrued on this task. The primary outcome on this task was the number of exploded balloons divided by 
the number of trials (Lejuez et al, 2002). 
 Immediate Memory Task / Delayed Memory Task (IMT/DMT): This task is a continuous performance task 
that has two phases. First, the IMT displays a series of five-digit numbers in on a computer monitor for 
500 ms followed by a blank screen 500 ms. Subjects click the mouse button whenever an identical 
number is displayed. Next, the DMT requires the subject to remember a five-digit number and compare it 
to another that is presented 3.5 seconds later. During the 3.5 interval subjects are presented with a 
distracter (12345) and told to ignore it. The primary outcome of this task is the IMT/DMT ratio which is 
defined as the proportion of commission errors to correct detections (Mathias et al 2002). This item is 
included as it we have used it in prior studies to identify menstrual phase differences in impulsivity and 
attention (see Preliminary Studies B.2.1.), and therefore is expected to be sensitive to the group 
differences in sex and progesterone. 
Our recently completed P20 studies indicate greater impulsivity as measured by delay discounting in cocaine 
subjects as compared to age and sex matched controls. Here comparisons will be made across the smoking 
only subjects in Project I, the cocaine+smoking subjects in Project II, and results of the animal models (Project 
III). The composite measures of impulsivity will include: 1) Self-report measures (BIS, BSCS), 2) Inability to 
delay gratification (delay discounting), 3) Inability to inhibit a prepotent motor response (GoStop task), 4) 
Inability to make choice to stop when reward becomes unlikely (BART), and 5) Immediate memory/delayed 
memory assessing cognitive processes (IMT/DMT). 
Independent Measures (sex, randomization and serum progesterone): Sex will be collected via self-report on 
the Demographics form completed at Screening Visit 1. Randomization, assignment (PRO vs. PBO) will be 
known as of the Baseline Visit to the SAC and Clinical Trials Research Pharmacy, but not will be unblended to 
other staff or participants until after completion of all measurements. Participants will be informed on their 
randomization assignment in a letter mailed within six months of the study’s completion; this letter will also 
briefly summarize the study’s findings. Measurement of serum progesterone will be measured by collecting a 
blood sample at clinic visits 0-4, 8 and 12. Blood (20 cc) will be drawn then centrifuged. The serum stored at -
20°C in sealed storage tubes to prevent evaporation. Approximately two mL of serum will be analyzed by the 
HealthEast Medical Laboratories for progesterone sample using chemiluminescence. The remaining serum 
(approximately two to four mL) will be used for estradiol measurement (described below) and/or stored as 
back-up to be used in the event that problems occur during analyses. 
Other Covariates: Information on potential covariates is collected at the clinic visits, including:  
 Smoking Behavior: Specifically, number of cigarettes smoked per day during ad libitum smoking, self-
reported number of past quit attempts, past longest quit attempt, motivation to quit smoking, and social 
influences such as partner smoking. This item will be completed at Screening Visit 1 only.  
 Fagerström Test for Nicotine Dependence (FTND; Heatherton et al 1991): This item will be administered 
during the first screening session to assess level of nicotine dependence. The FTND is a 6-item self-
report measure derived from the Fagerström Tolerance Questionnaire. This item will be completed at 
Screening Visit 1 only.  
 Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1998): This item includes 
measurement of: irritability, anger, anxiety, difficulty concentrating, restlessness, depressed or sad mood, 
and hunger. MNWS scores are calculated without the item of craving. We have changed the wording of 
the craving item to ’desire to smoke,’ and its mean scores are analyzed separately in light of evidence 
suggesting distinct patterns of craving from other withdrawal symptoms (Hughes & Hatsukami 1998). 
This item will only be completed once during the screening process.  This item will be completed at 
Screening Visit 1.  This item will be completed at each clinic visit thereafter.   
 Questionnaire for Smoking Urges (QSU-brief; Cox et al. 2001): This item is the shortened version of the 
QSU (Tiffany & Drobes, 1991) and will assess smoking urges. It includes 10 items clustered into two 
factors similar to those assessed by the longer version of QSU. Factor 1 includes items that indicate a 
strong desire and intention to smoke. Factor 2 includes items indicating expectation of a relief from 
negative affect with an urgent desire to smoke (Cox et al, 2001). This item will only be completed once 
during the screening process. This item will be completed at Screening Visit 1. This item will be 


Page 12 of 28 
completed at each clinic visit thereafter.   
 Profile of Mood States (POMS; McNair et al, 1971): On this 72-item form subjects use a 5-point Likert-
type scale, to indicate 10 subscales (Evans et al 1998) including positive mood, arousal, vigor, elation, 
friendly, fatigue, tension-anxiety, depression-dejection, confusion, and anger-hostility.  This item will only 
be completed once during the screening process. This item will be completed at Screening Visit 1. This 
item will be completed at each clinic visit thereafter.   
 Beck Depression Inventory-II (BDI-II, Beck et al, 1996): This is the most commonly used screening 
measure for adults and will be used to assess depressive symptoms. This item will only be completed 
once during the screening process.  This item will be completed at Screening Visit 1. This item will be 
completed at each clinic visit thereafter.   
 Perceived Stress Scale (PSS; Roberti et al, 2006): This ten item questionnaire will measure perceived 
stress. The items are rated on a 5-point scale, ranging from 0 (never) to 4 (very often), and they focus on 
events during the last week. The scale has adequate reliability and validity.  This item will only be 
completed once during the screening process. This item will be completed at Screening Visit 1. This item 
will be completed at each clinic visit thereafter.   
 Life Event Occurrence Survey (LEOS; McKee et al, 2005): This item will assess and account for the 
presence of current or recent significant life events. This measure includes 38 yes/no questions 
assessing various events that may have happened in the last six months including aspects of work, social 
life, family and finances. The measure includes instructions on how to rate the level of disruption the 
event caused in the subjects life from none too severe disruption. This measure will be administered at 
screening visit 1 and the final visit W12.    
 Columbia-Suicide Severity Rating Scale:  This questionnaire (C-SSRS; Posner et al, 2009) will be 
completed at each clinic visit to assess suicidal ideation, given this is listed as an SAE on the Prometrium 
label.  If any item of suicidality is endorsed referrals to the appropriate mental health care will be made.     
 Sociodemographic Variables: At the first screening visit we will collect information on age, race/ethnicity, 
education, income and other related variables. This item will be completed at Screening Visit 1 only. 
 Serum Estradiol: At Screening Visit 1 and clinic visits 0-4, 8 and 12, blood samples will be collected to 
allow for the measurement of serum estradiol. Following identical procedures described above for serum 
progesterone, approximately two mL of serum will be analyzed by HealthEast Medical Laboratories using 
chemiluminescence. 
 Leisure Time Exercise Questionnaire (LTEQ): This questionnaire has four-items to assess strenuous, 
moderate and mild exercise completed during leisure time and has high reliability (r=0.83, 0.85; Gordin & 
Shepard, 1985).   
 Caffeine Use:  Caffeine use will be collected via self-report at each clinic visit using the TimeLine 
FollowBack methods in which participants will report the total number of ounces of caffeinated beverages 
drank per day for each day. 
 Marijuana Use:  Marijuana use will be collected via self-report at each clinic visit using the TimeLine 
FollowBack methods in which participants will report number of days marijuana was used since the last 
clinic visit.  
 Adverse Childhood Experience (ACE):  Participants will complete this form at the SC2 visit. 
 Debriefing Questionnaire:  At end of study participation or Week 12, whichever is later, participants will 
complete a questionnaire to indicate which study medication (active or placebo) they thought they were 
on.  
 Pittsburgh Sleep Quality Index: This survey is a part of the SCOR Core Battery and will be used to 
facilitate collaboration across SCORs in the future. To be completed at SC2 visit 
 Quick Inventory of Depressive Symptoms: To be completed at SC2 visit 
 Anxiety: This survey is a part of the SCOR Core Battery and will be used to facilitate collaboration across 
SCORs in the future. To be completed at SC2 visit 


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 Quality of Life: This survey is a part of the SCOR Core Battery and will be used to facilitate collaboration 
across SCORs in the future. To be completed at SC2 visit 
 Body Map: This survey is a part of the SCOR Core Battery and will be used to facilitate collaboration 
across SCORs in the future. To be completed at SC2 visit 
 
B.4.7. Sample Size & Power Analysis  
We expect an approximate drop-out rate of 25% based on our current, more burdensome protocol within a 
sample of 18-40 year-old females. Therefore, we will enroll a total of 125 female and 125 male participants to 
ensure we have 100 per sex group to complete the 4 week follow-up for the primary outcome. Participants will 
be randomized 1:1 to PRO or placebo, separately by sex group, as described above. In our earlier work (Allen 
et al, 2008), the luteal quit group had a prevalence of 66% relapse at 30 days; this estimates the placebo group 
relapse rate for our proposed study. Based on a two-tailed Pearson chi-square test with alpha=0.025 for each 
sex group, a sample size of 100 completers per sex group will have 80% power to detect an odds ratio of 3.5 
or higher for comparing smoking relapse prevalence in the placebo group to smoking relapse prevalence in the 
PRO group. We observed an odds ratio of 3.2 for follicular quit group relapse compared to luteal quit group 
relapse (Allen et al, 2008). Since our PRO group will receive substantially more progesterone than the typical 
natural female cycle, it is reasonable to expect a slightly larger odds ratio for PRO compared to placebo. Since 
the difference in progesterone levels between the male PRO group and the male PBO group will be larger than 
the difference between the female PRO group and the female PBO group (see Figure 5), we expect a larger 
odds ratio (hence higher power) for the male treatment comparison. 
 
B.4.8. Statistical Analysis  
Randomization scheme: Our power calculation for the primary outcome specifies 100 males and 100 females. 
Since we expect approximately 25% drop-out before determination of the primary endpoint, we will over-enroll, 
approximately 125 of each sex. Thus we will build randomization tables for up to 150 male and 150 female 
potential enrollees. Each sex group will be randomized 1:1 to PRO vs. PBO. Since enrollment and 
randomization will occur over several years, we will employ a randomly permuted blocks allocation, rather than 
a simple random allocation, stratified by sex. This will reduce the possibility of a chance imbalance in treatment 
assignments, ensuring that we have treatment balance maintained within sex group consistently across the 
enrollment period. Block sizes of 4 and 6 will be used in a 1:1 ratio.  
Primary outcome analyses: This addresses Hypothesis 1. Our primary outcome is the binary indicator of 
relapsed yes/no at the week 4 visit. An unadjusted assessment of the treatment effect will come from a logistic 
regression of this binary outcome on randomized treatment assignment, separately by sex. The sex-specific 
treatment effect will be considered statistically significant if the p-value is <0.025. All persons randomized and 
with a measured primary outcome at the week 4 visit will be included in this analysis, regardless of whether or 
not they ever took any of their assigned treatment (intent-to-treat analysis); persons with missed visits are 
discussed below. While we expect baseline covariates to be balanced across treatment groups due to the 
randomization, an adjusted assessment of the treatment effect will then be carried out by a logistic regression 
including the randomized treatment assignment and pre-specified adjusting covariates such as age, baseline 
progesterone, estradiol, baseline impulsivity measures, etc. This pre-specified list will be determined by the 
study team during the finalization of the protocol, prior to the first study enrollment. We expect these analyses 
to be somewhat conservative, since they do not explicitly account for the randomized permuted blocking (Matts 
and Lachin, 1988). An analysis that accounts for the blocking (such as a stratified Mantel-Haenzel test) cannot 
be generalized to include the adjustment for impulsivity measures, for example, which are a focus of this 
proposal.  
Safety analyses: Adverse events will be quantified separately by sex and treatment groups and compared 
across treatment groups with Fisher’s exact test (for binary events) or with chi-square test (for counts of events 
or event rates). 
Secondary outcome analyses: These address Hypothesis 2. Our secondary outcomes include the binary 
indicator of relapsed yes/no at the week 12 visit, and days to relapse, as described above. The binary outcome 
will be analyzed as described for the primary outcome. Days to relapse will be analyzed using Kaplan-Meier 


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curves with a log-rank test comparing treatments (unadjusted) and Cox proportional hazards analysis (adjusted 
for other characteristics), both of which allow for loss-to-follow up via right censoring (Therneau and Grambsch, 
2000), separately for the CA and PA definitions. Adjusting variables will be selected as described for the 
primary outcome. The proportional hazards assumption on the treatment effect will be examined and tested 
(Lin, Wei, and Ying, 1993; Grambsch and Therneau, 1994). 
Other analyses: To address Hypothesis 3, we will pool the male and female data and test for an interaction 
between sex and treatment assignment in an adjusted Cox regression for the days to relapse outcomes. To 
address Hypothesis 4, we will test a baseline impulsivity by sex interaction in the logistic regressions for the 
binary outcomes and in the Cox regressions for the days to relapse outcomes. To address Hypothesis 5, we 
will test a baseline impulsivity by baseline serum progesterone interaction in the logistic regressions for the 
binary outcomes and in the Cox regressions for the days to relapse outcomes. While this study was designed 
to be powered for Hypothesis 1, rather than for these comparisons, these will be used to generate preliminary 
data and hypotheses for future research on sex differences in addiction treatment and impulsivity. 
Handling missing outcomes: For persons who do not attend a week 4 visit, assessment of the primary outcome 
is not directly possible. During their week 5, study staff will attempt to contact them in order to collect by phone 
and/or email a self-reported recall of smoking status as of week 4; outcomes collected in this way will be 
denoted separately in the study database. The primary outcome analysis will be carried out once excluding 
these persons, once including those for whom we were able to obtain a self-reported recall outcome, and once 
where we conservatively assume all these persons relapsed as of their week 4 visit. Since ‘missing at random’ 
is a strong statistical assumption to make in the primary outcome analysis, we will also carry out descriptive 
analyses to see whether persons missing their week 4 visit differed in their baseline characteristics or 
treatment assignment from persons not missing their week 4 visit. 
 
B.4.9. Existing Challenges & Barriers 
To test our study hypothesis in females, it is critical to produce and maintain serum progesterone levels 
consistent with those observed in the Luteal phase (6-14 ng/mL; Yee et al, 1999). To do this, we considered 
many different options for the delivery of exogenous hormones. First, we decided not to use combined 
synthetic progestin-estradiol hormonal contraceptive pills because this option would further complicate the 
study design by introducing another variable (exogenous estradiol; Goletiani et al 2007). Second, we also 
considered using synthetic progestin-only hormonal contraceptive pills. However, as we have observed in our 
current study, they also do not result in levels of serum progesterone consistent with the Luteal phase. Further, 
synthetic progestin has more risks associated it with it than natural progesterone (Goletiani et al 2007). Next, 
delivery of progesterone via intravaginal or rectal suppository, or intramuscular injection was eliminated 
because the serum progesterone levels would still be substantially lower than those typical of Luteal phase. 
Therefore, using natural micronized progesterone (generic Prometrium) is the best way to ensure serum 
progesterone levels remain consistent with levels observed during the Luteal phase. Since the half-life of 
natural progesterone is short, twice daily dosing is necessary. While there may be a question of subject 
compliance with taking two oral doses per day, we will confirm compliance via the assessment of serum 
progesterone levels at all study visits postpartum. Natural progesterone is also the easiest way to administer 
supplemental progesterone for male participants and has been successfully done in other studies (Goletaini et 
al 2007). On a related note, a second challenge is estrogen. Estrogen fluctuates naturally during the menstrual 
cycle (Yee et al 1999), and has also been shown to be associated with the facilitation of drug abuse behaviors 
(Carroll & Anker, 2010). While it is impossible to remove estrogen from our sample population, we will measure 
it (via blood samples to measures serum estradiol levels) and consider it in our analyses.  
 
B.4.10. Timeline 
The 
study 
timeline 
is 
displayed in Table 2.  
 
B.4.11. Future Directions 


Page 15 of 28 
The expected outcomes of this project will be a better understanding of the relationship between sex, sex 
hormones, impulsivity and smoking behavior. Upon completing this project, we intend to continue our 
exploration into the role of sex hormones on smoking behavior. Specifically, if our expectations are confirmed, 
we plan to conduct a similar study in a time associated with increased risk for smoking relapse for both men 
and women – the postpartum period.  
 
 


Page 16 of 28 
C.  Inclusion of Children.   
Children (under 18 years old) are not included since young age is associated with menstrual cycle irregularities 
(e.g., anovulation).  Further, since this study requires the continuous (or a recent history) of regular use of 
cigarettes, it is unlikely adolescents will meet this criterion.  Young men and women (e.g., aged 18-20 years) 
will be recruited for participation in our study.  The trial site is at the University of Minnesota, which has a large 
undergraduate population. Campus media will be also used to recruit young men and women.  We will also 
target venues and institutions frequented by young non-college men and women (bars, festivals, coffee shops, 
and community events) to ensure the sociodemographic diversity of the youngest component of our participant 
sample.  
 
 
 
D.  Inclusion of Women and Minorities 
This study will be recruiting both men and women because the research question addressed is designed to 
assess sex differences.  We are looking specifically at the effects of a female sex hormone (progesterone) on 
smoking cessation in men and women who are motivated to quit smoking.  The study will use participants 
recruited from the greater metropolitan area of Minneapolis and St. Paul, via mass media advertisements.  The 
Twin Cities metropolitan area has a sufficiently large female smoking population to ensure an adequate 
sample.  We have been successful in recruiting similar numbers of women in similar periods of time in previous 
studies.  Estimates indicate that as of 2009 the Minneapolis and St. Paul, Minnesota Twin Cities metro area 
included approximately 50.5% female and 20.2% of the population in the racial minority groups (Black= 11.0%, 
Asian = 5.8%, American Indian = 1.2%, other = 4.0%) and the Hispanic population is 6.4%.   If minority women 
do not respond to the advertisements, we will make special efforts to solicit their participation by advertising in 
local neighborhood newspapers with high minority readership (such as the Southside Pride, Phillips/ 
Powderhorn, and Riverside Editions); by posting flyers in free clinics in the metro area who service minorities 
(e.g., Community University Healthcare Center, Pilot City); and by identifying contacts in churches, health 
centers, and community centers with high minority participation and disseminating information regarding the 
study opportunity; and once we have garnered initial contact with participants we receive multiples word of 
mouth referrals.  Our current study has been successful in recruiting a diverse sample in that of the 163 
participants enrolled to date 49% are White, 33% are Black, 8% are more than one race and 10% are other.  
 
 


Page 17 of 28 
 
Data Safety and Monitoring Plan (DSMP): 1 P50 DA033942-01 
PROJECT 1 – Sex Differences and Progesterone: 
Association with impulsivity and smoking cessation 
 
Summary 
This is one of two clinical trials for the SCOR entitled: Sex Differences and Progesterone Effects on Impulsivity, 
Smoking, & Cocaine Abuse. The DSMP is described below. Organization and implementation of the Data Safety and 
Monitoring Board functions will be administered by the Service Core (B) of the P50 (Grabowski, Director). This will be 
undertaken in close coordination with the Principal Investigators of the two clinical Projects (Drs. Allen and Specker) 
and the overall SCOR Director (Dr. Carroll), co-Director (Dr. Allen) and study staff members.   
A1. Study Design and Implementation 
This is a 12-week, two arm (progesterone-PRO- versus 
placebo-PBO), prospective, parallel groups, 
randomized placebo-controlled trial examining effects 
of PRO, compared to placebo (PBO), as well as sex 
differences on impulsivity and smoking cessation 
outcomes in females and males who are motivated to 
quit smoking. 
Outcome Measures 
The primary focus and outcome measure will be 
prevalence of smoking relapse at Week 4 using point 
prevalence definition of abstinence.  This will be 
measured via self-report, carbon monoxide 
breathalyzer, and urinary cotinine.  Secondary outcome measures include days to relapse (also measured by self-
report, carbon monoxide breathalyzer, and urinary cotinine using continuous abstinence and prolonged abstinence 
definitions) and impulsivity measures (self-report questionnaires including Behavioral Inhibition / Activity Scales, 
Barratt Impulsiveness Scale, and Brief Self Control Scale; and computer tasks including Delay Discounting, GoStop 
Task, Balloon Analogue Risk Task, and Immediate/Delayed Memory Task). 
Setting, Recruitment, Subjects 
Setting: This project will be conducted at the Delaware Clinical Research Unit (DCRU). The DCRU has both inpatient 
and outpatient resources for the spectrum of biomedical research including special capabilities that were developed 
for study of substance use disorders. The Clinical and Translational Sciences Institute (CTSI), runs the DCRU and 
functions parallel and support the activities of the NIH funded CTSA, which predated it. The DCRU includes: reception 
area, examination rooms, meeting rooms, clinical interview rooms, testing rooms for computer based performance 
tasks, a wet lab for handling bloods and other specimens, freezers (to -80°C), all essential staff offices, each with 
multiple telephone and computer lines through the University of Minnesota servers, a locked limited access protocol, 
equipment and medication rooms, as well as secure cabinets for study files and essential supply and support areas 
and services. 
Recruitment: To meet recruitment goals, we will enroll a total of 250 subjects (~6 subjects/month) to ensure a final 
sample size of 100 females and 100 males. Our primary recruitment method will be advertising in the mainstream 
media. While this type of recruitment can be challenging, our team has been successful with this form of recruitment. 
For example, our current study recruiting females between the ages of 18-40 has had success with Facebook 
advertising. Specifically, over the past seven months we have advertised on Facebook resulting in 6,483 clicks to our 
website, an estimated 180 phone calls to our clinic and an enrollment of 29 subjects (~4 subjects/month). We regularly 
use television, radio, mailings, and other internet sources to identify study subjects with similar success.  Using all of 
these methods, we have successfully enrolled ~8 subjects/month over the past year in our two ongoing tobacco use 
research studies. Additional advertising and the unique character of this study will further assure an ample sample.  
Subjects and Eligibility Criteria 
Two hundred and fifty subjects, 50% female, will be consented to achieve the final sample of 200 subjects (50% 
female). The inclusion and exclusion criteria are: 


Page 18 of 28 
Inclusion Criteria 
1. 
Males between 18 and 60or females between 18 and 50 years of age;  
2. 
Self-reporting smoking ≥ 5 cigarettes/day for at least the past year;  
3. 
Motivated to quit smoking (self-report ≥ 7 on 10-point Likert-type scale);  
4. 
Stable physical/mental health;  
5. 
Self report of regular menstrual cycles (female only);  
6. 
Willing to use a double-barrier contraception method if sexually active and not surgically sterilized;  
7. 
English fluency;  
8. 
Understanding the study procedures and able to provide informed consent; 
9. 
Ability to participate fully in research elements for the duration of the trial. 
Exclusion Criteria 
1) 
Current use of other types of tobacco, nicotine replacement therapy, or smoking cessation medications;  
2) 
Current or recent (< 3 months) breastfeeding (females only),  
3) 
Current or planned pregnancy within the next three months (females only);  
4) 
DSM-IV diagnoses for, bipolar disorder, ADHD, or major depressive disorder within the last 3 month. 
5) 
 Substance dependence within the last 3 month with the exception of nicotine dependence and non-daily use 
of marijuana. 
6) 
Use of psychotropic medications;  
7) 
Current use of exogenous hormones, finasteroid (propecia), efavirenz, red clover, ketoconazole and other 
drugs that are CYP3A4 inhibitors  
8) 
Conditions contraindicated to progesterone treatment (including, but not limited to, thrombophlebitis, deep vein 
thrombosis, pulmonary embolus, clotting or bleeding disorders, heart disease, diabetes, history of stroke, allergy to 
peanuts, hypersensitive to progesterone and liver dysfunction). 
Screening and Visit Procedures 
The first clinic visit (i.e. Screening Visit 1) will occur within seven days of the onset of menses in females and within 
two weeks of the telephone interview for males. A brief description of the study will be provided to determine if the 
subject wishes to proceed with the informed consent process. If agreeable, the informed consent process will be 
initiated with the candidate subject. Responses will be provided to all candidate subject queries. If the subject agrees 
to participate, she or he will sign the consent, be provided with a copy of the signed document, and screening will be 
initiated. Screening will determine final eligibility as determined by meeting inclusion criteria without any exclusionary 
conditions. Screening will include a general medical examination including history, measurements of height, weight, 
blood pressure, heart rate, and expired carbon monoxide will be obtained.  Female subjects will provide a urine 
sample that will be used for a pregnancy test. A blood sample will be obtained to assess serum hormone levels and 
and a psychiatric interview will be completed by trained study staff.  Subjects will complete forms to measure smoking-
related symptomatology, mood, and potential confounders (i.e. age, education, partner smoking, motivation to quit 
smoking, level of nicotine dependence).   At the end of this visit subjects will schedule their next visit and receive 
compensation for their time. 
The second visit (i.e. Screening Visit 2), completed within three days of Screening Visit 1, will include a series of 
computer tasks to measure impulsivity, followed by training on study procedures and compensation for their time. 
A Baseline Visit will occur seven days prior to the subjects assigned quit date.  Females will have their assigned quit 
date set seven to nine days after ovulation.  Ovulation will be determined through the use of urine ovulation tests that 
female subjects will use daily for ten days in a row.  Males will have their assigned quit date matched to a female 
subject for a similar delay and procedure completion. At this visit subjects’ weight, blood pressure, heart rate, and 
carbon monoxide level will be measured.  They will also provide urine and blood samples (20cc) for later 
measurement of nicotine exposure (specifically nicotine and cotinine) and hormone levels (specifically progesterone 
and estradiol), respectively.  At this visit subjects will receive their study medication and be provided 
regimen/administration instructions.  They will also receive brief smoking cessation behavioral counseling, be 
compensated for their time, and receive a schedule of all follow-up visits.   
At the follow-up visits (weekly visits, Week 0 - Week 12) all subjects will have their weight, blood pressure, heart rate 
and expired carbon monoxide measured.  The subjects will provide urine (nicotine, cotinine) at all visits and blood 
(progesterone, estradiol) samples at visits 0-4, 8 and 12 and complete several forms to measure smoking-related 
symptomatology, mood, and related items.  The study nurse will assess their adverse events.  At the end of each visit 
subjects will receive additional behavioral counseling, additional study medication and be compensated for their time. 


Page 19 of 28 
Subjects could earn up to $480 for their study participation ($25 for screening visit x 2 screening visits + $20 for 
baseline visit + $20 for follow-up clinic visits x 13 visits + $75 bonus for missing less than three visits + $75 for 
completing the study).   
Power Analysis and Sample Size 
We expect an approximate drop-out rate of 25% based on our current more burdensome protocol within a sample of 
18-40 year-old females. Therefore, we will enroll a total of 125 female and 125 male participants to ensure we have 
100 per sex group to complete the 4 week follow-up for the primary outcome. Participants will be randomized 1:1 to 
PRO or placebo, separately by sex group, as described above. In our earlier work (Allen et al, 2008), the luteal quit 
group had a prevalence of 66% relapse at 30 days; this estimates the placebo group relapse rate for our proposed 
study. Based on a two-tailed Pearson chi-square test with alpha=0.025 for each sex group, a sample size of 100 
completers per sex group will have 80% power to detect an odds ratio of 3.5 or higher for comparing smoking relapse 
prevalence in the placebo group to smoking relapse prevalence in the PRO group. We observed an odds ratio of 3.2 
for follicular quit group relapse compared to luteal quit group relapse (Allen et al, 2008). Since our PRO group will 
receive substantially more progesterone than during the typical natural female cycle, it is reasonable to expect a 
slightly larger odds ratio for PRO compared to placebo. Since the difference in progesterone levels between the male 
PRO group and the male PBO group will be larger than the difference between the female PRO group and the female 
PBO group, we expect a larger odds ratio (hence higher power) for the male treatment comparison. 
B. TRIAL MANAGEMENT 
Enrolling Clinics and Data Collection 
Centers.  All study subject enrollment and 
data collection will be done at the Delaware 
Clinical Research Unit at the University of 
Minnesota. 
Projected Timetable.  The projected 
timetable is displayed in Table 1. 
Target Population Distribution.  This study will be recruiting both men (n=100) and women (n=100) because the 
research question addressed is designed to assess sex differences.  Specifically, the effects of a female sex hormone 
(progesterone) on smoking cessation in men and women who are motivated to quit smoking will be examined.  Study 
participants will be recruited from the greater metropolitan area of Minneapolis and St. Paul, via mass media 
advertisements.  Estimates indicate that as of 2009 the Minneapolis and St. Paul, Minnesota Twin Cities metro area 
included approximately 50.5% female and 20.2% of the population in the racial minority groups (Black= 11.0%, Asian 
= 5.8%, American Indian = 1.2%, other = 4.0%) and the Hispanic population is 6.4%.  In the absence of minority 
population response to advertisements, additional targeted strategies will be implemented to solicit their participation.  
These efforts are effective; for example, our current study has been successful in recruiting a diverse sample: 49% are 
White, 33% are Black, 8% are more than one race and 10% are other.  


Page 20 of 28 
Enrollment Table 
 
C. DATA MANAGEMENT AND ANALYSIS 
Data Acquisition and Transmission.  Data collection at study visits will take the form of subjective measures (forms), 
blood and urine samples, and will be identified with a three-digit identification number.  Samples will be collected and 
stored with the subject ID code only.  The coordinator will keep the code that links the subject ID with the identity of 
the subject in a database protected by two-levels of security stored it separately from the data.   
Data Entry Methods.  All self-report data collection items throughout the study will be self-administered per direction of 
study staff via a computer program (REDCap; http://project-redcap.org/) to improve the quality of data (by avoiding 
missing data, illegible data, etc) and limit the time spent on data entry and cleaning.  Any data not entered directly into 
a computer system (i.e. height, weight, blood pressure) will be double entered on our password protected server by 
trained data entry personnel at the Tobacco Research Programs using the Access data entry programs.  The study 
coordinator will be available to monitor the data and correct any discrepancies based on source documents.   
Data Analysis Plan.  Addressing Hypothesis 1: Our primary outcome is the binary indicator of relapsed yes/no at the 
week 4 visit. An unadjusted assessment of the treatment effect will come from a logistic regression of this binary 
outcome on randomized treatment assignment, separately by sex. The sex-specific treatment effect will be considered 
statistically significant if the p-value is <0.025. All persons randomized and with a measured primary outcome at the 
week 4 visit will be included in this analysis, regardless of whether or not they ever took any of their assigned 
treatment (intent-to-treat analysis); persons with missed visits are discussed below. While we expect baseline 
covariates to be balanced across treatment groups due to the randomization, an adjusted assessment of the 
treatment effect will then be carried out by a logistic regression including the randomized treatment assignment and 
pre-specified adjusting covariates such as age, baseline progesterone, estradiol, baseline impulsivity measures, etc. 
This pre-specified list will be determined by the study team during the finalization of the protocol, prior to the first study 
enrollment. We expect these analyses to be somewhat conservative, since they do not explicitly account for the 
randomized permuted blocking (Matts and Lachin, 1988). An analysis that accounts for the blocking (such as a 
stratified Mantel-Haenzel test) cannot be generalized to include the adjustment for impulsivity measures, for example, 
which are a focus of this proposal. 
Hypotheses: 


Page 21 of 28 
 
Addressing Hypothesis 2: Our secondary outcomes include the binary indicator of relapsed yes/no at the week 12 
visit, and days to relapse, as described above. The binary outcome will be analyzed as described for the primary 
outcome. Days to relapse will be analyzed using Kaplan-Meier survival curves with a log-rank test comparing 
treatments (unadjusted) and Cox proportional hazards analysis (adjusted for other characteristics), both of which allow 
for loss-to-follow up via right censoring (Therneau and Grambsch, 2000), separately for the CA and PA definitions. 
Adjusting variables will be selected as described for the primary outcome. The proportional hazards assumption on the 
treatment effect will be examined and tested (Lin, Wei, and Ying, 1993; Grambsch and Therneau, 1994). 
To address Hypothesis 3, we will pool the male and female data and test for an interaction between sex and treatment 
assignment in an adjusted Cox regression for the days to relapse outcomes. To address Hypothesis 4, we will test a 
baseline impulsivity by sex interaction in the logistic regressions for the binary outcomes and in the Cox regressions 
for the days to relapse outcomes. To address Hypothesis 5, we will test a baseline impulsivity by baseline serum 
progesterone interaction in the logistic regressions for the binary outcomes and in the Cox regressions for the days to 
relapse outcomes. While this study was designed to be powered for Hypothesis 1, rather than for these comparisons, 
these will be used to generate preliminary data and hypotheses for future research on sex differences in addiction 
treatment and impulsivity. 
D. QUALITY ASSURANCE 
Data collected via computer programs (EMAs and REDCap) will be monitored by the study coordinator by random 
inspection of completed forms, and any problems detected will be discussed with the PI.  The Statistics Core (Eberly, 
Director) will analyze the data using the SAS program.  In addition, the Statistics Core will provide support in 
developing data entry programs.  Data analyses will be completed at the end of the study.  For missing data: Persons 
who do not attend a week 4 visit, assessment of the primary outcome is not directly possible. During their week 5, 
study staff will attempt to contact them in order to collect by phone and/or email a self-reported recall of smoking 
status as of week 4; outcomes collected in this way will be denoted separately in the study database. The primary 
outcome analysis will be carried out after excluding these subjects, including those for whom we were able to obtain a 
self-reported recall outcome, where we conservatively assumed all these individuals relapsed as of their week 4 visit. 
Since ‘missing at random’ is a strong statistical assumption to make in the primary outcome analysis, we will also carry 
out descriptive analyses to see whether persons missing their week 4 visit differed in their baseline characteristics or 
treatment assignment from persons not missing their week 4 visit. 
E, Regulatory Issues: Adverse Events, Serious Adverse Events, Collection and Reporting 
Adverse Events: An adverse event is any unwanted experience or event occurring during the course of a clinical trial.  
At each visit, either a research nurse or physician will query the participant and log side effects and other treatment 
emergent events since the past visit, recording their severity (mild, moderate, severe, life-threatening), what action 
was taken, and whether the symptoms are continuing or resolved. The study investigators will follow all AEs to the 
point of a satisfactory resolution.  A study subject may be withdrawn from the study if the PI determines it is the best 
decision for protection of the safety of the subject.  All AEs will be assessed to determine if they meet criteria for an 
SAE.  AEs will be quantified separately by sex and treatment groups and compared across treatment groups with 
Fisher’s exact test (for binary events) or with chi-square test (for counts of events or event rates).  The event will be 
documented as to whether there is 1) no relationship between the study drug and the adverse event, 2) the adverse 
event is unlikely related to administration of the study drug, 3) the adverse event is possibly related to study drug 
administration, or 4) the adverse event is probably related to the administration of the study drug.  
Serious Adverse Events (SAE): A serious adverse event is defined as an outcome that is 1) fatal or life-threatening, 2) 
significantly or permanently disabling or incapacitating, 3) requires or prolongs inpatient hospitalization, or 4) results in 


Page 22 of 28 
a congenital anomaly. SAE’s, whether or not related to study medication, will be reported to the IRB and NIDA. All 
drug related adverse events of a non-serious nature are reported to the University of Minnesota’s IRB on a quarterly 
basis.  Serious adverse events will be reported by telephone to the IRB, and to NIDA and the FDA within the three 
days of our receipt of information regarding the event and written reports will be submitted within ten days.  If a subject 
either withdraws from the study or the investigator decides to discontinue a subject due to SAE, the subject will have 
appropriate follow-up medical monitoring.  Monitoring will continue until the problem requiring hospitalization was 
resolved or stabilized with no further change expected, is clearly unrelated to study medication, or results in death.  
Outcome of SAEs will be periodically reported to NIDA.  A summary of the SAEs that occurred during the previous 
year will be included in the annual progress report to NIDA.  Finally, the PI’s will ensure that serious adverse events 
reported to NIDA via the serious adverse event tracking and reporting system at https://saetrs.nida.nih.gov/. 
The Principal Investigator will then take appropriate action (including study modification) as agreed upon by these 
monitoring groups including the DSMB when needed.  The Principal Investigator will determine whether the 
seriousness of the event warrants removal of the participant from the study.  Appropriate diagnostic and therapeutic 
interventions will be initiated and the participant will be medically followed and kept under observation as long as 
medically indicated. After the review of the data, the DSMB report will make recommendations about whether the trial 
should continue with or without modifications, or be terminated. Any potential conflict of interest in the Data and Safety 
Monitoring Board will be disclosed.  
F. Trial Safety 
Potential Risks and Benefits for Participants.  The potential risks for study subjects are minimal to moderate.  Medical 
histories for all subjects will be reviewed prior to entry into the study and all subjects will be under medical supervision 
while in the study.  Urine and breath samples will be obtained and should not present risk to the subjects.  Blood 
samples will be obtained by trained phlebotomists.  A minimal amount of blood will be collected (20cc) per collection. 
Blood drawing may result in slight discomfort, bruising, or there may be some soreness at the puncture site. In some 
cases there may be dizziness or fainting.   
Generic Prometrium, a natural progesterone, is generally well tolerated.  The most common adverse effect is sedation. 
Other less common adverse effects include menstrual irregularity, spotting or breakthrough bleeding, dizziness, 
cramps, nausea, fatigue, headache and breast tenderness (de Lignieres, 1999; Simon, 1995, Sofuglu, 2009). Other 
side effects attributed to synthetic progesterone, including depression, fluid retention, pruritus, jaundice, rash and 
thrombotic disorders, are unlikely to occur.  Recently there have been reports of increased risk of stroke, coronary 
artery disease, venous thromboembolism and breast cancer in postmenopausal females who have been on long-term 
hormone replacement treatment with estradiol and progestin (medroxyprogesterone) combination (Anonymous, 2002; 
Grady et al., 2002; Hulley et al., 2002; Nelson et al., 2002). While some of these adverse events develop after years of 
treatment, venous thromboembolism is seen within the first year of treatment (Anonymous, 2002). It is possible that 
progestins may contribute to thromboembolism seen during estradiol and progestin treatment and thromboembolism is 
listed in the PDR as one of the adverse events for medroxyprogesterone treatment (PDR, 2002). In contrast to 
synthetic progestins, natural progesterone is not known to cause thromboembolism (PDR, 2002). However, as a 
safety measure for these serious adverse events, we will exclude subjects with history of thrombophlebitis, deep vein 
thrombosis, pulmonary embolus, clotting or bleeding disorders, heart disease, diabetes or history of stroke. Possible 
adverse events from generic Prometrium will be assessed weekly by the research nurse (Schulz, NP) in consultation 
with the study physicians (Allen MD, Specker MD).  If the side effects cannot be tolerated the medication dosage will 
be decreased to 200 mg daily.  
Although uncomfortable, withdrawal symptoms do not pose significant health risks.  Subjects who participate in this 
study will be asked to quit smoking on an assigned quit date.  The smoking abstinence may result in increased 
irritability, anxiety, tension, depression, increased hunger or drowsiness.  
a. Recruitment and Informed Consent.  Subjects will be recruited via metro mass media advertisements (television, 
radio, print, email, and internet). Those who see the mass media advertisements will contact Tobacco Research 
Programs in response to advertisements.  Each subject interested in participating will be screened by telephone 
interview for eligibility.  If eligible, subjects will be asked to attend a screening visit.  At this visit subjects are provided 
with a detailed explanation of the study purpose and procedures (including risk involved), any questions a subject may 
have will be answered, subjects will be asked questions to assess their understanding of the study, and informed 
consent will be obtained before any study procedures are completed. 
b. Protection against Risk.  Subjects will be told the potential risks involved in this study.  Although risks to subjects in 


Page 23 of 28 
the proposed study are minimal, the following actions will be taken to minimize these risks.  We will exclude subjects 
with health conditions that may be exacerbated by their participation.  Subjects will be monitored regularly by medical 
personnel employed by the study.  Dr. Sharon Allen (PI) will be available for emergency phone calls 24 hours/day and 
for office visits in case of problems.  Blood will be collected by trained phlebotomists to reduce the risks involved with 
blood draws.   
During generic Prometrium administration, the first dose of the study medication will be taken at 8 PM to minimize 
possible sedation from initiation of progesterone treatment. Subjects will be warned about using caution when driving 
a motor vehicle or operating machinery. Subjects will also be warned about the side effects associated with generic 
Prometrium.  Further, although unlikely, the study physician (Dr. Allen, PI) will be alert to the earliest manifestations of 
thrombotic disorders including thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal 
thrombosis (PDR, 2002). If any of these occur or are suspected, the study medication will be discontinued immediately 
and medical treatment will be sought.  
There may be risk to confidentiality and privacy of study data.  To minimize this risk, subjects will be assigned unique 
three-digit identification numbers.  The questionnaires and study samples will retain only the unique study number.   
These numbers will be linked to the subject’s identifier information in a database separate from assay results or other 
data collected.  The database requires at least 2 levels of security (i.e., passwords), which will allow only authorized 
research team members to access the information.   
Potential Benefits of the Proposed Research to the Subjects and Others 
Whereas no assurance can be made to an individual subject that he/she will personally benefit from such research, 
the experience should be beneficial.  Subjects will have the opportunity to learn about their smoking behavior and 
receiving smoking cessation behavioral counseling.   Society may benefit from a better understanding of the role of 
sex and sex hormones on smoking behavior and impulsivity.  A better understanding of this relationship will help 
improve treatment strategies for nicotine dependence. The risks in relation to the potential benefits are minimal to the 
individual research subject and virtually nonexistent to society in general.   
G. Trial Efficacy 
No interim analyses of efficacy are planned for the proposed study.  
H. Data Safety and Monitoring Plan, Board, and Administration.  
The Service Core (Grabowski, Director) of the P50 will implement the plans and organize review by the Data Safety 
and Monitoring Board (DSMB). The Service Core (B) will administratively oversee the DSM Plan, Board and complying
with reporting requirements. This provides additional separate attention to, monitoring and focus on safety. The DSMB 
will meet annually and will, post meeting, provide a summary of discussion, which will be conveyed to NIDA. This repor
will include subject demographics, expected versus actual recruitment rates, summary of any quality assurance or 
regulatory issues, summary of adverse events (AEs) or serious adverse events (SAEs) which may have occurred, and 
any changes in the protocol as a result of these issues. The DSMB will receive current data and blinded data unless a 
specific request or cause to view unblinded data is evident. The final report will be complete and inclusive with the 
unblended data set. 
The Service Core Project Manager (A. Allen) will meet with the Study Coordinator (D. Babb) and PI (S. Allen) on a 
weekly basis to review the study’s progress.  Additionally, the Service Core Director (J. Grabowski) will also be 
available to identify and solve problems in the study’s implementation, as well as advise on any adverse events 
experienced by subjects during the study. Drs. Grabowski, Allen (PI Project 1) and Specker (PI Project 2) will meet 
regularly and as needed regarding data and project safety. Additionally, all key personnel will meet regularly regarding 
overall progress, specific problems and problem resolution. The daily monitoring of subjects will be the coordinator’s 
responsibility.  The coordinator will also report to the Project Manager and PI as needed. 
Participants will be closely monitored throughout the trial. A summary of all data, with the exception of information that 
entails breaking the blind, will be provided to the DSMB at annual meetings. SAE’s will be reported to the head of the 
DSMB when they have been identified and characterized. The chair of the DSMB may request a special meeting of 
the panel as needed. The Board will consist of Drs. Frances Levin, Dr. Scott Crow and Dr. Sofuoglu. These individuals 
will serve to monitor SCOR projects involving human subjects.  
The group will meet on an annual basis and review data including recruitment, progress, safety, adverse events, and 
serious adverse events associated with the study. The DSMB meeting will include open, closed and executive 


Page 24 of 28 
sessions. The Principal Investigator, co-investigators, and statisticians will attend the open session and present during 
the meeting. The purpose of the open session is to provide relevant information to the Board about general aspects of 
the trial. The open session will focus on the background of the study, the protocol, status of the study, problems with 
accrual and follow-up, baseline demographic data, compliance issues, frequency of adverse events, documentation of 
endpoints, data quality issues, flow of forms, data based protocol modification issues, and any other issue regarding 
the studies under review that can be discussed without reference to interim comparative results. 
Following the open session, a closed session will be held. During the closed session, the chairperson (Frances R 
Levin MD) will conduct the review of all issues and puts each issue to a vote. This session will be attended by the 
DSMB members and if necessary the statistician, principal investigator. During the closed session, the discussions will 
focus on the treatment safety, requesting and reviewing additional information if needed and updating the Board on 
actions taken related to their actions and recommendations of the previous meeting. 
Following the closed session, an executive meeting may be held. The executive meeting will be restricted to DSMB 
members. During these sessions, the Board may discuss any sensitive issues surrounding the clinical trials under 
review. 
The Board Chairperson will prepare a draft report of the meeting along with minutes for inclusion in the final DSMB 
report. The report will outline and summarize discussion during the open and closed sessions of the meeting. 
Recommendations and action items will be clearly marked within the body of the report. If the DSMB conducts an 
executive session, a statement will be included in the Minutes of the Meeting stating that an executive session was 
conducted, but content of the discussion will be retained by the chair and not included in the report. The draft report 
shall be reviewed and edited by all Board members prior to issuance of the final report. 
If deemed necessary, the DSMB can request to know whether or not the participant received active medication or 
placebo. If they believe that termination of the trial is warranted, the blind of all study participants will be broken. 
DSMB recommendations will be communicated to the NIDA Project Officer soon after the DSMB meetings.  
 
Affiliation and contact information for the DSMB members are listed below: 
Frances R Levin MD, Professor 
Department of Psychiatry 
Columbia University 
New York Psychiatric Institute, Unit 66 
1051 Riverside Drive 
New York, NY 
Tel: 212 543 5896 
Email: frl2@columbia.edu 
 
Scott Crow MD, Professor 
Professor 
Department of Psychiatry F282/2A West 
University of Minnesota 
2450 Riverside Drive 
Minneapolis MN 55454 
Tel: 612-273-9807 
Email: crowx002@umn.edu 
 
Mehmet Sofuoglu MD 
Associate Professor 
Department of Psychiatry 
Yale University 
MPSY VA/Substance Abuse 
34 Park St 
New Haven, CT 06519-1187 
Tel: 203-937-4809 
Email: mehmet.sofuoglu@yale.edu 
 


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Reference:  
The data safety and monitoring plan is based on the investigators experience, expertise and the template developed 
by Dr. Ivan Montoya, NIDA/NIH.  
http://www.drugabuse.gov/funding/clinical-research/guidelines-developing-data-safety-monitoring-plan 
 


Page 28 of 28 
SCOR P1 and MJ 
 
 
Rules/Changes 
 
 
 
 
 
 
 
               Last Updated: 9/8/16 
 
 
In order to be eligible at BL, subject must be averaging 4.5 CPD for the past 2 weeks.  If a subject is smoking less 
than 4.5 CPD, they will be dropped from the study and filed as “SCREEN FAIL” (1/1/15). 
 
 
Week 0 clinic visit must be completed on the subject’s quit date.   If this is not possible, it may be completed 
AFTER the quit date but a protocol deviation must be made.  Week 0 cannot be completed BEFORE quit date 
(1/3/15). 
 
 
Subjects are allowed to miss 2 clinic visits over the entire study to eligible for the $75 bonus at Week 12 – unless 
a cancelation was made by study staff (instead of the subject).  That absence would NOT count against the 
bonus (1/29/15). 
 
 
ALT/AST levels must not be higher than double the normal range to be enrolled at SC.  If levels are higher than 
double the normal range, the subject will be notified of the results, referred to PCP for follow-up and invited 
back in 4 weeks to re-test.  If levels are high but within double the normal range, the subject may be enrolled 
per Dr. Allen’s approval.  He/she will be tested again at Week 1 and as long as levels have not gone up, they will 
be allowed to continue in the study (1/29/15). 
 
 
The last available time to start a follow-up appointment will be 5:00pm (Week 4, 8, 12 – 4:30pm) 
 
 
We will only collect 2 urine samples at each visit (00 & 01) (4/7/15). 
 
 
Samples to be sent for analysis: 
Hormones   
BL 
W4 
W12 
(Blood) 
Cotinine 
 
W4 
W12 
(Blood) 
 
 
BDI scores will be monitored weekly by study staff.  If a subject scores ≥20 or endorsed suicidal thoughts 
(Question #9), staff will start an AE and continue to monitor scores.  If score decreases and is <14 after three 
weeks with no suicidal thoughts, the AE may be closed.