Conditions: Smoking Cessation
Keywords: Smoking Cessation Nicotine Cessation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: no

Brief summary:
This will be a double-blind, placebo-controlled, pilot, randomized clinical trial. A total of 50 women who smoke and have regular menstrual cycles will be randomized to either progesterone (200 mgs BID) + Transdermal Nicotine Patch (TNP) or placebo + TNP for 8 weeks. TNP will be tapered after 4-6 weeks. Progesterone or matching placebo will be discontinued at the end of Week 8. All participants will also be provided behavioral treatment for smoking cessation. Participants will be inducted onto progesterone (or placebo) + TNP over a one-week period (Week 1) during the mid luteal phase, within a week before menses and the target quit date will be set for the 5 (+/-2) days after onset of menses. Participants will have post-trial follow-up visits at 1 and 3 months.The main study outcomes will be self- report of smoking abstinence, biochemically verified smoking abstinence, measures of cigarette craving and nicotine withdrawal, and measures of response inhibition.

Detailed description:
This study seeks to determine if modifying the hormonal milieu of the menstrual cycle, through administration of exogenous progesterone, will improve the effectiveness of treatments for smoking cessation in women. Progesterone, a gonadal hormone, is used clinically for treatment of endometrial hyperplasia, amenorrhea, dysfunctional uterine bleeding, and for assisted reproduction in women. Progesterone also shows promise for the treatment of multiple central nervous system disorders including cocaine addiction, seizure disorder, and traumatic brain injury. As the next step, the investigators seek to determine if progesterone augments standard smoking cessation treatments (e.g., NRT) in regularly cycling women. The investigators hypothesize that co-treatment with progesterone, compared to placebo, will enhance the effectiveness NRT for smoking cessation. To test this hypothesis, the investigators propose an 8-week, double-blind, placebo-controlled clinical trial, which will randomize 50 smokers using a 1:1 assignment ratio to 400 mg/day progesterone or placebo. Consistent with the Clinical Practice Guidelines, all participants will also receive transdermal nicotine patch (TNP) plus brief counseling for smoking cessation during the study participation.

Specific Aim #1: To determine if progesterone +TNP is superior to placebo +TNP for prolonged and 7-day point prevalence of smoking abstinence rates at the end of 8 weeks of treatment and at 1 and 3 month follow-up time points. The investigators will also evaluate the safety and tolerability of progesterone treatment, compared to placebo. Our co-primary outcome measures will be 7-day point prevalence of smoking abstinence and breath CO at the end of treatment and 1- and 3-months after the end of the trial. Specific Aim #2: To determine if progesterone + TNP treatment, compared to placebo + TNP, improves response inhibitory function, as assessed by the Stroop, The Go/No Go task, and the Digit Symbol Task. Specific Aim # 3: To determine if progesterone + TNP treatment, compared to placebo + TNP, leads to a greater reduction in cigarette craving and nicotine withdrawal symptoms, as assessed by the Questionnaire on Smoking Urges-Brief (QSU-B) and the Minnesota Nicotine Withdrawal Scale (MNWS), respectively. Specific Aim #4: To evaluate with affective changes, as shown on the Positive and Negative Affect Schedule, mediates the effects of progesterone on smoking abstinence.

Arms:
arm 1: Transdermal Nicotine Patch + Progesterone (200 mgs BID) arm 2: Transdermal Nicotine Patch + Placebo (for Progesterone)

Interventions: intervention 1: Progesterone (200 mgs BID) intervention 2: Placebo
Intervention descriptions: intervention 1: Transdermal Nicotine Patch (TNP) + Progesterone intervention 2: TNP + Placebo

Protocol document:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     Application to Involve Human Subjects in Biomedical Research
100 FR1 (2013-1) 
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: Progesterone Augmentation of Nicotine Replacement Therapy Study 
Principal Investigator: Kimberly Ann Yonkers, 
MD  
Yale Academic Appointment: Professor
Department: Psychiatry
Campus Address: 40 Temple Street, Suite 6B, New Haven, CT 06516
Campus Phone: 203-764-
5914
Fax: 203-764-6766
Pager: 
E-mail: 
Kimberly.yonkers@yale.edu
Protocol Correspondent Name & Address (if different than PI):
 
Campus Phone: 
Fax: 
E-mail: 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
Yale Academic Appointment:
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html 
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.  
HIC OFFICE USE ONLY
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Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes
No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes
No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the form:  
http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
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1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael Campus
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location:
40 Temple Street, Suite 6B
1 Long Wharf, New Haven
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories
 Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
 International Research Site 
(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date: 
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 
3. Research Type/Phase: (Check all that apply)
a. Study Type
   
 Single Center Study
   
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
  
 Coordinating Center/Data Management
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 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c:
 Clinical Research: Patient-Oriented
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral 
                Health Services
 Translational Research #1 (“Bench-to-Bedside”)    
 Interdisciplinary Research
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Upon funding will be registered in clinical trials. 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
 contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
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a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study.
Yes 
 No
If you answered "yes", this study will need to be set up in OnCore Support
http://medicine.yale.edu/ymg/systems/ppm/index.aspx 
8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No __X_  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? N/A 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? No
 
c. Will a novel approach using existing equipment be applied? N/A
 
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Kimberly 
Yonkers, MD
Progesterone 
Augmentation for 
Smoking Cessation in 
Women
National Cancer Institute 
R21CA198187
 Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
 Grant-M# 160200          
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
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  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify: 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name:
Company:
Address:
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below.
Name
Affiliation: Yale/Other 
Institution (Identify)
NetID
Principal Investigator 
Kimberly Yonkers, MD
Yale
Role: Co-Investigator
Mehmet  Sofuoglu, MD
Yale
Role: Co-Investigator
Aileen Gariepy, MD
Yale
Role: Co-Investigator
Haiqun Lin, MD
Yale
Role: Co-Investigator
Ariadna Forray, MD
Yale
Role: Biostatistician
Kathryn Gilstad-Hayden
Yale
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NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT
Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      prtigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
___
__
9/11/2015
 
PI Name (PRINT) and Signature
Date
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 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
For HIC Use Only
Date Approved
Human Investigation Committee Signature
This protocol is valid through ______________________________________________
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SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
This pilot randomized clinical trial will test whether modifying the hormonal milieu during the 
menstrual cycle through administration of exogenous progesterone will augment the 
effectiveness of NRT for smoking cessation in regularly cycling women. Our study hypothesis 
regarding progesterone’s augmentation effects are supported by systematic studies conducted 
by our group and others. Findings from this study may lead to novel treatment approaches 
tailored specifically to female smokers
This study seeks to determine if modifying the hormonal milieu of the menstrual cycle, through 
administration of exogenous progesterone, will improve the effectiveness of treatments for 
smoking cessation in women. Progesterone, a gonadal hormone, is used clinically for treatment 
of endometrial hyperplasia, amenorrhea, dysfunctional uterine bleeding, and for assisted 
reproduction in women. Progesterone also shows promise for the treatment of multiple central 
nervous system disorders including cocaine addiction, seizure disorder, and traumatic brain 
injury (1, 2). The utility of progesterone for smoking cessation is suggested by a number of 
previous studies. In a clinical trial, progesterone dominance during the luteal phase of the 
menstrual cycle, as compared to estrogen dominance in the follicular phase, significantly 
enhanced smoking abstinence in women attempting to quit smoking (3). Our group conducted 
pioneering human studies to determine the safety and potential efficacy of progesterone for the 
treatment of nicotine addiction. In these studies, progesterone, compared to placebo, attenuated 
the pleasurable effects of cigarette smoking or intravenously administered nicotine in abstinent 
smokers (4, 5). Progesterone also reduced craving for cigarettes and improved response 
inhibitory function in abstinent female smokers (6). These findings are promising because 
attenuating nicotine reward, and improving withdrawal symptoms and response inhibition are 
potential treatment targets for nicotine addiction (7, 8). As the next step, we seek to determine if 
progesterone augments standard smoking cessation treatments (e.g., NRT) in regularly cycling 
women. We hypothesize that co-treatment with progesterone, compared to placebo, will 
enhance the effectiveness NRT for smoking cessation. To test this hypothesis, we propose an 
8-week, double-blind, placebo-controlled clinical trial, which will randomize 50 smokers using a 
1:1 assignment ratio to 400 mg/day progesterone or placebo. Consistent with the Clinical 
Practice Guidelines (9), all participants will also receive transdermal nicotine patch (TNP) plus 
brief counseling for smoking cessation during the study participation. The dose of TNP will be 
21mg/24 hours for 4 weeks, 14mg for weeks 5 and 6 and 7 mg for weeks 7 and 8 for women 
who smoked at least 10 cigarettes per week.  We will start a 14 mg/day dose of TNP for women 
who smoke less than 10 cigarettes per week.
Specific Aim #1: To determine if progesterone +TNP is superior to placebo +TNP for prolonged 
and 7-day point prevalence of smoking abstinence rates at the end of 8 weeks of treatment and 
at 1 and 3 month follow-up time points.  We will also evaluate the safety and tolerability of 
progesterone treatment, compared to placebo.  Our co-primary outcome measures will be 7-day 
point prevalence of smoking abstinence and breath CO at the end of treatment and 1- and 3-
months after the end of the trial.
Specific Aim #2: To determine if progesterone + TNP treatment, compared to placebo + TNP, 
improves response inhibitory function, as assessed by the Stroop, The Go/No Go task, and the 
Digit Symbol Task.  
Specific Aim # 3: To determine if progesterone + TNP treatment, compared to placebo + TNP, 
leads to a greater reduction in cigarette craving and nicotine withdrawal symptoms, as assessed 
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by the Questionnaire on Smoking Urges-Brief (QSU-B) and the Minnesota Nicotine Withdrawal 
Scale (MNWS), respectively.
Specific Aim #4:  To evaluate with affective changes, as shown on the Positive and Negative 
Affect Schedule, mediates the effects of progesterone on smoking abstinence.
Exploratory Aim: We will evaluate the degree to which serum estradiol and progesterone levels 
achieved during the trial are associated with a) greater smoking abstinence, b) improved 
response inhibition, and c) less craving and withdrawal symptoms.  
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
Nicotine addiction continues to be the main preventable cause of death in developed countries, 
with an estimated 435,000 premature deaths in the U.S and 5 million deaths worldwide (11). 
About 18% of women and 22% of men in the US smoke (11). Some evidence suggests that 
women respond less favorably to NRTs, even though they maintain their nicotine addiction with 
lower levels of nicotine intake than men (12-15). Women, compared to men, may be more 
vulnerable to the complications of smoking, most notably lung cancer (16, 17). In the US, lung 
cancer kills more women than the breast and colon cancer combined. These findings support 
the need to develop more effective treatments tailored for female smokers.
Current pharmacological treatments for smoking cessation: Current first line treatments for 
smoking cessation include NRT (including nicotine gum, lozenge, inhaler and spray), bupropion, 
and varenicline (10, 18). With some minor differences, these treatments increase the odds of 
quitting smoking by 2 to 3 fold (19, 20). Still, this only translates to smoking abstinence at one 
year for 10%-30% of smokers who attempt to quit. Combination treatments may be more 
effective than a single agent for smoking cessation suggesting that there is room for improved 
efficacy among smoking cessation treatments(21). Unfortunately, concerns about the 
neuropsychiatric adverse effects of varenicline and bupropion, especially suicidal ideation and 
behavioral changes, limit their use alone or in combination with other medications (22). Among 
NRTs, there are no significant differences between different products in their efficacy for 
smoking cessation (23). Transdermal nicotine patch (TNP) has advantages over other NRTs for 
its consistent delivery of nicotine for 24 hours, ease of use and favorable adverse effect profile.
Role of sex hormones in addictive behaviors: Both estradiol and progesterone have well-
documented actions on multiple neurotransmitters affecting the brain reward pathway (24). 
While estradiol activates the reward pathway, progesterone has the opposite effects (25). For 
example, in the mid-follicular phase of the human menstrual cycle (when progesterone is low 
and estrogen is high), as compared to the progesterone dominant luteal phase, the reward 
circuitry (midbrain, striatum, and left fronto-polar cortex) is more highly activated (26).
As summarized below, the therapeutic potential of sex hormones, especially progesterone, 
suggest that progesterone may have a role in treatment of nicotine addiction in female smokers 
(27).
Progesterone as a neurosteroid: Progesterone is a hormone produced by male and female 
gonads, adrenal glands and in the brain by oligodendrocytes and neurons (hence the moniker 
“neurosteroid”) (28). In premenopausal women, progesterone levels are low in the follicular 
phase of the menstrual cycle, and are comparable to those in men, < 1 ng/ml (29). Women have 
higher progesterone levels than men during the luteal phase of the menstrual cycle (2-28 
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ng/ml), and during pregnancy (9 to 200 ng/ml) (30). Progesterone and its metabolites interact 
with multiple neurotransmitter receptors including GABAA, glycine, sigma1, kainate,
serotonin3, and nicotinic receptors (31). Among these actions, the best studied are the effects of 
progesterone on the GABA receptors. Progesterone’s active metabolites, pregnanolone and 
allopregnanolone, have positive modulatory effects on GABAA receptors, and enhance GABA 
transmission (31). This may lead to reduced nicotine reward given the inhibitory actions of 
GABA on dopamine release in nucleus accumbens, a key step in mediating reward (32).
Endogenous progesterone modulates nicotine addiction: Many preclinical studies demonstrate 
that progesterone administration reduces the rewarding effects of cocaine (33, 34). Although the 
actions of exogenous progesterone on nicotine reward have not been assessed (27), Lynch (35) 
showed that in adolescent rats that are trained to self-administer nicotine, levels of responding 
under a progressive-ratio schedule are negatively associated with plasma progesterone levels. 
These results support an inhibitory influence of progesterone on nicotine self-administration.
In a human laboratory study using an ad lib smoking paradigm in female smokers, a lower 
progesterone to estrogen ratio was associated with greater number of puffs and increased puff 
intensity (36). Similarly, in a clinical trial, Allen et al. (4) randomized 200 women to quit in 
follicular or luteal phase of the menstrual cycle. Women who quit in the follicular phase relapsed 
faster to smoking than those who quit during the progesterone dominant luteal phase ((OR) = 
2.87, 95% CI= 1.47– 5.59). The effect was robust; at 30 days the odds of remaining abstinent 
for the luteal phase group was 3.18 (95% CI= 1.59–6.34) higher than the follicular phase group. 
This same group showed that abstinence during the luteal phase of the cycle was accompanied 
by increases in allopregnanolone.(37) Mazure et al. (38) produced similar findings using 
bupropion. However, there are divergent findings (39, 40) that may be a result of differing study 
methods. Our proposed study will help clarify the literature by providing exogenous 
progesterone rather than relying on timing of the menstrual cycle to infer hormone levels.
Progesterone as a treatment for nicotine addiction. Our group has conducted a series of 
pioneering studies demonstrating the safety and potential effectiveness of progesterone for the 
treatment of nicotine addiction in women. In our initial study (5), we found that oral 
progesterone, compared to placebo, attenuated the craving for and pleasurable or hedonic 
effects from smoking in 12 female smokers. In our next study, we confirmed these findings 
using our intravenous nicotine administration paradigm (6). We observed that progesterone 
attenuated the pleasurable effects of intravenous nicotine in abstinent 12 male and female 
smokers.
We have also evaluated underlying mechanisms of the potential therapeutic effects of 
progesterone (7). We found that 400 mg of progesterone treatment, administered for four days, 
reduced urges to smoke in female abstinent smokers. Further, progesterone treatment 
improved performance in the Stroop and the Digit Symbol Substitution Test (DSST) but the 
effect on the Stoop performance was sex specific in that only women (n=30) showed 
improvement. Given that the Stroop test is a measure of ability to inhibit pre-potent responses, 
our findings suggest that progesterone improves response inhibition in abstinent female 
smokers (7).Our findings are consistent with preclinical and clinical suggesting that 
progesterone improves response inhibition or impulsive behavior which may contribute to its 
proposed efficacy for smoking cessation (41, 42).
Safety of Progesterone: Progesterone is used treat a variety of gynecological and obstetrical 
disorders. Although extensive first pass effects limited oral use, oral micronized progesterone 
formulations are now FDA approved. The safety and tolerability of micronized progesterone is 
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well established (43, 44). The most common adverse effect of progesterone is mild sedation. 
Other less common adverse effects include menstrual irregularity, spotting or breakthrough 
bleeding, dizziness, cramps, nausea, fatigue, headache, and breast tenderness (44, 45). In our 
previous studies, micronized progesterone has been well tolerated without any serious adverse 
events (2, 5-7, 46-49).
Progesterone is commonly confused with progestins, a group of synthetic progesterone analogs 
that include medroxyprogesterone and norethindrone, are included in most oral contraceptives 
and some hormone replacement therapies. Progestins differ from natural progesterone in their 
pharmacological properties and side effect profiles. Most progestins, but not progesterone, have 
well-characterized androgenic, glucocorticoid, and anabolic effects and have been associated 
with unfavorable side effects including fluid retention, alterations in lipid profile, and increase risk 
for breast cancer and cardiovascular events. These side effects are not associated with natural 
progesterone treatment (50-52). An additional key difference between progesterone and most 
progestins is that the former, but not the latter, are metabolized to pregnanolone and 
allopregnanolone, which, as noted above, have significant GABAergic and other CNS effects. 
Consistent with these distinctions, progestins and progesterone differ in their influence on many 
CNS functions including learning, memory, and reward functions (53). Finally, progesterone (but 
not progestins) is also under investigation for the treatment of cocaine addiction, seizure 
disorder, and traumatic brain injury (54, 55).
Summary of the rationale: Progesterone’s capacity to attenuate smoking urges, to diminish the 
positive subjective effects of smoking, and to improve cognitive performance all point to its 
potential therapeutic value for smoking cessation. Because smoking urges predict relapse to 
smoking, progesterone-related attenuation supports its potential efficacy for smoking cessation 
(56). Greater positive subjective effects from smoking before a quit attempt or during a lapse 
also predict relapse to smoking (57, 58). Similarly, improvement of cognitive function in 
association with progesterone use, especially with regard to response inhibition is a potential 
mechanism for the proposed efficacy of progesterone for smoking cessation (59).
b) Innovation
A number of current researchers are exploring combined treatment for smoking cessation. 
Targeting the hormonal milieu to develop novel treatments for female smokers is a novel new 
direction. Although previous studies compared the different phases of menstrual cycle for 
smoking cessation outcomes, no previous study has directly modified the hormonal milieu. 
Second, the use of progesterone as an adjunct to NRT for smoking cessation is innovative. This 
study will translate findings from pre-clinical and human laboratory studies into treatment 
development by testing the efficacy of progesterone for smoking cessation in a clinical trial. 
Third, we also propose to evaluate response inhibition as the cognitive mediator of 
progesterone’s therapeutic effects on nicotine addiction. Data on response inhibition will shed 
light on how, as well as if, progesterone is effective in this population. Lastly, we will assay 
hormone levels to provide a direct assessment of the role of gonadal steroids (estrogen and 
progesterone) on likelihood of smoking abstinence.
Previous research
As summarized above, our human laboratory and outpatient studies have demonstrated the 
safety and potential efficacy of micronized progesterone for smoking cessation in regularly 
cycling women.
We have extensive experience in recruiting and conducting clinical trials with pre-menopausal 
cigarette smokers. Dr. Sofuoglu is an expert in medications development and laboratory studies 
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for medications development; Dr. Yonkers is an expert in treatment of women with mental 
health and addiction problems (see attached biosketches). She has conducted numerous 
menstrual cycle studies as well as studies on women and addiction. As an example of our 
successful collaboration, we have completed the first study examining progesterone’s safety 
and effectiveness in postpartum women with cocaine used disorder (2).
We have successfully recruited and retained women in prior studies. In a study of progesterone 
for treatment of postpartum cocaine users (R21 DA029914), we recruited the targeted 50 
women and retained 82% in a 12- week clinical trial. In an ongoing study, R01 DA034243 we 
have recruited 423 women, including more than 250 reproductive aged women who smoke, to a 
randomized clinical trial of screening, motivational interviewing and referral to substance abuse 
treatment. Retention at 1, 3 and 6 months has been 86%, 83% and 83%, respectively.
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. Describe the setting in 
which the research will take place.
Overview of the study design 
This will be a double-blind, placebo-controlled, pilot, randomized clinical trial. A total of 50 
women who have regular menstrual cycles will be randomized to either progesterone (200 mgs 
BID) + Transdermal Nicotine Patch (TNP; 21 or 14 mg/day) or placebo + TNP (21 mg or 
14mg/day) for 8 weeks. TNP will be tapered after 4-6 weeks as recommended by the Clinical 
Practice Guidelines for treating tobacco dependence (9). Participants who smoke more than 10 
cigarettes per day will receive the following dose of TNP: 21mg/24 hours for 4 weeks, 14mg for 
weeks 5 and 6 and 7 mg for weeks 7 and 8. Participants who smoke between 5-10 cigarettes 
per day will receive the following dose of TNP: 14mg/24 hours for 6 weeks, 7mg for weeks 7 
and 8.
Study medications will be discontinued at the end of Week 8. All participants will also be 
provided behavioral treatment for smoking cessation. Participants will be inducted onto 
progesterone (or placebo) + TNP over a one-week period (Week 1) during the mid luteal phase, 
within a week before menses and the target quit date will be set for the 5 (+/-2) days after onset 
of menses. Participants will have post-trial follow-up visits at 1 and 3 months following the end 
of the trial. The main study outcomes will be self- report of smoking abstinence, biochemically 
verified smoking abstinence, measures of cigarette craving and nicotine withdrawal, and 
measures of response inhibition.   
Human subjects
Recruitment: Recruitment will take place over 1.5 years, requiring enrollment of approximately 
2-3 subjects per month. In our previous studies, we have been able to recruit on average 4 
female smokers per month. Recruitment is further explained in Humans Subjects but will be 
accomplished by direct screening in our reproductive health centers (20% of women seen for 
services in these centers are smokers), direct mail invitations,posters and flyers placed in local 
obstetrician-gynecologist offices. We have successfully used these techniques to recruit 
substance users, smokers and women with premenstrual dysphoric disorder in prior clinical 
trials. Dr. Yonkers has a secondary appointment in Obstetrics & Gynecology and has conducted 
numerous studies that entailed screening women in the reproductive health settings of Yale 
New Haven Hospital and their faculty (see Biosketch).
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Update June 2017: All participants had blood levels of progesterone drawn. We were blind to 
assignment of participants but at the end of the study found that those who were randomized to 
active progesterone had low progesterone levels. This could be due to the progesterone 
preparation or the fact that smokers metabolize it very quickly. In any case, the low progesterone 
levels in the active treatment group obviates our ability to test our hypothesis that progesterone 
augmentation assists abstinence for smokers. Given the lack of funds, we cannot repeat the 
project. Rather, we are recruiting a second cohort and are using a commercially available oral 
micronized progesterone rather than the previous medication that was compounded for the study. 
We plan to enroll a minimum of 12 people with an imbalanced ratio of 6 active to 1 placebo.
We will continue to obtain plasma levels of progesterone. This will enhance our ability to test 
our hypothesis. If need be in a final analysis, and give that this is a pilot project, we may be able 
to use the participants randomized to placebo in the first cohort and second cohort and the 
participants randomized to active in the second cohort. 
Update September 2017:  We request an additional blood draw (timeline is around Visit #6 or #7 
to confirm progesterone plasma levels and compliance with pill taking. The second blood draw 
will be the same as the first one, completed at a professional lab on the first floor of the research 
site building. Approximately 6 ccs of blood will be drawn for each.
Urn Randomization:  To increase the likelihood that the two groups are balanced for age and the 
amount of smoking, participants will be assigned to the two study conditions through “urn” 
randomization (Stout et al, 1994). A categorical variable will be created based on the number of 
cigarettes/day in the month before randomization: 1=<15; and 2=≥15 or more cigarettes on 
average, per day, to distribute severity of smoking evenly over the two groups.  
Update June 2017: We plan to enroll a minimum of 12 people with an imbalanced ratio of 6 
active to 1 placebo.
We will post the study on the research team’s website www.ResearchForHer.com, YCCI’s Help 
Us Discover database, and on Yale’s Department of Psychiatry Website as well as other 
websites. We will also include the study in some of Yale’s online newsletters.
Study Procedures
Recruitment:  Women will be recruited by word of mouth, flyer, advertisement, direct screening 
and online postings.  Women will be contacted by telephone or seen face to face if the 
screening is direct.  We will obtain verbal consent from the potential participant to conduct a 
brief, preliminary screen.  Women will be asked if they smoke at least 5 cigarettes, are receiving 
any medical treatment for smoking cessation, use hormonal contraceptives, use illicit 
substances, have regular menstrual cycles.  No PHI will be collected for women who are 
ineligible at this point, although we will keep a list of women who were screened and ineligible 
so that they will not be screened again.  We will also keep a de-identified (not linked) list of 
reasons for non-participation. Women who are provisionally not eligible or interested will be 
provide referrals if desired.  Women who are provisionally eligible will be undergo the 
consenting procedure and they will be offered a face to face appointment to complete screening 
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and baseline assessments. If they are screened face-to-face we will obtain consent at this point 
and set a face-to-face assessment visit.   
Determination of Eligibility and Baseline Visit: This interview will occur between estimated days 
18-24 of the typical menstrual cycle.  This will be a 120 minute visit. It will be broken down into 
two parts: 1) we will determine eligibility for the randomized clinical trial (RCT) and 2) we will 
obtain baseline measures for those who are eligible.  The first procedure will be obtaining 
informed consent (please see consent procedures below).  In the process of consent, we will 
explain to the provisionally eligible participant that part of the visit will be to determine eligibility 
for the RCT.  For determination of eligibility, women will complete the NIDA Quickscreen (10); 
DSM 5 psychosis screener and DSM 5 screener for major depressive disorder, panic disorder 
or post-traumatic stress disorder (PTSD; current).  Any positive responses on these measures 
will trigger an evaluation, including the SCID and assessment by a study clinician (a physician 
for medical issues; a psychologist, physician or social worker if the issues is an exclusionary 
psychiatric diagnosis) that will indicate whether or not the participant is eligible; 2) a medical 
history will be gathered to obtain information on allergies, especially progesterone, use of 
medication, pregnancy planning, history of breast cancer, deep vein thrombosis, coagulation 
problems, liver failure, cervical intraepithelial neoplasm, allergy to nuts, etc; and 3)  nicotine 
intake history including use of all nicotine products, number of cigarettes smoked and use of 
other nicotine products in the previous month, prior treatment for smoking cessation; prior 
intolerance or allergy to transdermal nicotine patch; 4) laboratory tests that include urine for 
pregnancy, cotinine and drugs of abuse and expired breath CO.  
The RA will complete a checklist that indicates eligibility criteria.  The checklist will be reviewed 
by study clinician who will confirm that this information has been gathered and that the 
participant meets criteria for participation.  For women who continue to be eligible, the RA 
and/or study clinician will ask baseline measures that include: 1) a menstrual history form 
including module for diagnosis of premenstrual dysphoric disorder and menstrual cycle dating, 
the Fagerstrom Test for Nicotine Dependence (FTND) (11); the Minnesotal Nicotine Withdrawal 
Scale (MNWS) (12), the Questionnaire on Smoking Urges-Brief (QSU-B) (13) and the Positive 
and Negative Affect Schedule(14) .  They will also complete the following neurocognitive tasks: 
1) the Stroop, (15) 2) Go/No Go, 3) Digit Symbol SubstitutionTest (part of the WAIS III), 4) The 
Shipley Institute of Living Scale (SILS) is a paper-and-pencil, self-administered scale that 
consists of a 40-item vocabulary and a 20-item pattern recognition section (16).
Randomization/Visit 1: After eligibility is confirmed and the baseline assessments are 
completed, women will be randomized.  Women will then begin smoking cessation counseling 
and will receive two weeks supply of their study medication, TNP + either oral micronized 
progesterone or placebo.  They will be instructed to apply one nicotine patch /day and to take 
one pill twice daily after the visit.  They will be instructed to set a quit date for the 5 (+/-2) days 
after the onset of menses, ideally around the 3-4th day when perimenstrual symptoms have 
abated and before estrogen peaks. We will call them at the estimated time of menses onset to 
confirm dates and quit date plans. We used similar strategies in smoking studies and menstrual 
cycle studies (6). 
Treatment Phase (Visit 2 to 8):  Women will be seen for follow up around days 7-11 of their 
menstrual cycle, shortly after their quit date. This visit will confirm that treatment with TNP + 
progesterone or placebo was initiated and maintained for the estimated 2 weeks since 
Visit 1.  Medication compliance will be assessed by pill count.  Support and counseling will be 
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provided for the quit attempt. Assessments will be repeated although the neurocognitive battery 
will only be done a second time at this first follow up visit. A blood draw will be completed twice 
throughout the study, the first around Visit #2 and the other around Visit #6 or Visit #7 at a 
professional lab on the first floor of the research site building. Approximately 6 ccs of blood will 
be drawn for each.
Other assessments will be conducted weekly for the additional  weeks of the study. 
Assessments will include a weekly calendar of cigarettes smoked, if any, breath CO. We will 
collect urine for cotinine if the breath test is negative and there are concerns about compliance 
with TNP.  If there is a possibility that a participant is pregnant (i.e. she is not menstruating or in 
the week following menstruation) we will also test urine for positive pregnancy. Additionally, 
subjects will have brief behavioral treatment sessions for smoking abstinence. 
End of study (Visit 8), Termination and follow-up: At the end of the 8-week treatment period, 
participants will complete their weekly ratings, collect breath CO. Participants and study staff will 
be asked to guess their treatment condition (progesterone or placebo) and will discontinue study 
capsules and TNP. All participants will be encouraged to remain abstinent from smoking (9). 
Follow-up visits will be scheduled at 1 and 3 months after the end of the study.  At follow up, 
assessments of smoking and the PANAS will be repeated.  We will not repeat the neurocognitive 
measures.
Strategies to minimize attrition and enhance follow up: We will: 1) rapidly assign study 
treatments after application confirmation of eligibility, 2) thoroughly explain study treatments and 
requirements, and 3) specify uniform procedures across treatment conditions regarding study 
staff’s handling of participants who miss or come late to sessions. Study investigators will 
monitor participants who drop out and explore with the staff reasons for the dropouts. We will 
follow the full randomized sample, regardless of their retention in treatment, by including: 1) a 
thorough explanation at the consent interview of the importance of follow-ups, 2) collecting at 
least three verified locators who are likely to have knowledge of a subject’s whereabouts, 3) 
paying participants to cover transportation and parking for follow-up visits. 
Treatment Conditions
Transdermal Nicotine Patch (TNP): TNP has been studied extensively as a smoking cessation 
treatment.   Meta-analyses find that there is little difference among the types of NRTs although 
the patch provides a constant and slow delivery of nicotine. (17) The 24-hour delivery system 
is available in 7-, 14-, or 21-mg doses. Smokers who smoke more than 10 cigarettes/day 
begin with a 21-mg/d nicotine patch for the first 4 weeks and switch to 14 mg/d on weeks 5 
and 6, and to 7 mg/d on weeks 7 and 8. Smokers who smoke between 5-10 cigarettes/day 
begin with a 14-mg/d nicotine patch for the first 6 weeks and switch to 7 mg/d on weeks 7 and 
8. TNP is generally well-tolerated and has few side effects (skin irritation, nausea, vomiting, 
sweating, mood and sleep disturbances). In addition, once-daily dosing may lead to better 
compliance. Neither longer term (> 8 weeks) nor a higher dose (> 21 mg/d) of nicotine patch 
improves efficacy over the standard treatment (17). 
Progesterone: The recommended dose of progesterone for hormone replacement treatment is 
200 to 400 mg/day. We chose the 200 mgs BID because at this dose progesterone improved 
cognitive performance (6) but was associated with lower craving scores. After oral 
administration, micronized progesterone reaches its peak plasma levels in two to three hours 
and has an elimination half-life of three to four hours (18). Because of the short half-life of 
micronized progesterone, progesterone will be given twice daily to maintain stable plasma 
level of progesterone.
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Strategies to protect the blind: 1) Randomization will be done by computer and will be 
maintained by the statistician. Study staff will only have access in cases of medical emergencies 
or after the study. 2) Placebo and progesterone will be packaged in similar appearing capsules. 
3) Hormone levels will be sent from the lab directly to the study statistician. 4) Participants will 
meet weekly with the study team for medication dispensing and for monitoring of adverse 
events. Any gynecological adverse events will be followed up immediately and independently by 
a gynecological consultant (Dr. Gariepy) and reviewed at regular staff meetings. Dr. Gariepy will 
not share the gynecological adverse events with the rest of the team except if the blind needs to 
be broken for safety reasons. 5) At the end of each patient’s treatment, we will also ask the 
study team members (as well as the participants) to guess whether patients were on 
progesterone or placebo.
Behavioral Platform: All study participants will receive standard behavioral treatment consistent 
with current clinical practice guidelines for smoking cessation (9). Participants will be provided a 
booklet, “Clearing the Air” (19) at the beginning of the trial and will be asked to bring it to their 
weekly sessions. Behavioral treatment sessions will prepare participants for quit day and provide 
skills to prevent relapse to smoking. These sessions will be brief, 10 to 15 minutes, and cover the 
topics that are outlined in the booklet. The topics include: 1) reasons to quit smoking, 2) preparing 
to quit smoking, 3) alternatives to smoking, 4) preventing relapse, 5) focus on new healthier 
lifestyle, 6) preventing weight gain, 7) long term benefits of quitting smoking and focus on the 
future. Participants who relapse will be encouraged to set a new quit date and attempt to quit 
smoking.   
Training of Research Personnel: The research associate will have at least a Bachelor’s level 
education and previous experience in clinical rating and interviewing. All staff will receive one 
month of training on the substance use calendar, expired CO and collection of other scales 
under the supervision of an experienced clinician. Training includes observation of interviews 
and ratings, co-rating, and interviews with supervisors (project director and Dr. Yonkers).  
Behavioral treatment will be audiotaped (with informed consent of the subject) for therapist 
supervision and adherence ratings. Dr. Yonkers will provide supervision and feedback.
4. Genetic Testing   N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will 
be received
iii. the types of information about the donor/individual contributors that will be 
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
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F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
Please see detailed inclusion/exclusion criteria noted below.  In general, otherwise healthy, 
regularly-menstruating female smokers that do not have a history of major medical or 
psychiatric illnesses will be recruited for this study.
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements)
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
Inclusion criteria: a) Aged 18 - 45; b) smoking at least 5 cigarettes/ day for at least one year; 
c) regular menstrual cycles every 24–36 days for the previous 6 months; d) motivated to quit 
smoking (i.e., a rating of at least “7 “on a 10-point scale where 1 is not at all motivated and 
10 is extremely motivated); e) in good health; and f) using an acceptable, non-hormonal 
birth control. 
Exclusion criteria: a) a history of major medical illnesses including liver diseases, heart 
disease, diabetes, malignancy including history of breast cancer, deep vein thrombosis, 
blood coagulation problems including a history or family history of thrombophilia, use of an 
antithrombotic agent, liver failure, cervical intra-epithelial lesions III or greater that are 
untreated, allergy to peanuts or other nuts, or other medical conditions that the physician 
investigators deems will make study participation unsafe for the subject; b) current or past 
history bipolar disorder or schizophrenia or current diagnosis of major depression, panic 
disorder or post-traumatic stress disorder; c) use of all non-nicotine drug substances are 
excluded at the mild DSM-V diagnosis; alcohol use is excluded at the moderate DSM-V level 
diagnosis (caffeine use is not evaluated or excluded); d) currently undergoing treatment with 
another pharmacological agent for smoking cessation; e) daily use of sedating medications 
including sleeping aids  and others; f) use of nicotine from cigars, pipes, chewing tobacco, 
e-cigarettes; g) pregnant, breast- feeding or intending to become pregnant within 6 months 
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and; h) allergy to nicotine patch or progesterone.
8. How will eligibility be determined, and by whom? 
Women who are provisionally eligible after screening will be seen for a confidential, in office 
assessment.  We will have a checklist that study staff complete at the baseline assessment 
visit that lists eligibility/ineligibility criteria.  The PI or PI-s designee must check the 
participant’s document, verify the checklist and confirm eligibility according to inclusion and 
exclusion criteria.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Progesterone, a natural hormone, is safe and well-tolerated by women. The safety, 
tolerability and efficacy of micronized progesterone is well established and it is FDA 
approved for hormone replacement therapy (HRT), absence of menstrual periods 
(amenorrhea), endometriosis, infertility treatment and preterm delivery. The recommended 
dose of progesterone for hormone replacement treatment is 200 to 400 mg/day, given as a 
single evening dose. After oral administration, micronized progesterone reaches its peak 
plasma levels in two to three hours and has an elimination half-life of three to four hours 
(18). Because of its short half-life progesterone will be given twice daily to maintain stable 
plasma levels. Progesterone doses higher than 400 mg/day will not be used since they are 
more likely to cause sedation. The safety and tolerability of micronized progesterone are 
well established. We have used micronized progesterone in several previous studies with 
female smokers (4-6). Progesterone was well-tolerated and we did not encounter any 
serious adverse events. The most common adverse effect is mild sedation. Other less 
common adverse effects include menstrual irregularity, spotting or breakthrough bleeding, 
dizziness, cramps, nausea, fatigue, headache and breast tenderness. Other side effects 
attributed to synthetic progestins, including depression, fluid retention, pruritus, jaundice, 
rash and thrombotic disorders, have not been observed with natural progesterone. Women 
will be warned to use caution when driving a motor vehicle or operating machinery while 
undergoing study treatment.
There is black-box warning for progesterone regarding the risk for cardiovascular 
disorders and breast cancer. The black box warning mentions the Women’s Health 
Initiative (WHI) study in which treatment of postmenopausal women (50 to 79 years of 
age) with daily oral conjugated estrogens combined with medroxyprogesterone acetate 
(MPA), relative to placebo, reported increased risks of deep vein thrombosis, pulmonary 
embolism, stroke, and myocardial infarction (20). The pharmacological effects of MPA, a 
progestin, differ substantially from those of progesterone. MPA, but not progesterone, has 
well-characterized androgenic, glucocorticoid and anabolic effects and have been 
associated with unfavorable side effects including fluid retention, androgenic effects, 
alterations in lipid profile, increase risk for breast cancer (21, 22), and cardiovascular 
events (23). In contrast to MPA, progesterone is not known to cause these adverse events 
(24). 
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10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
As a safety measure for these serious adverse events, we will exclude subjects with 
history of nut allergy, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting 
or bleeding disorders, heart disease, diabetes or history of stroke, breast cancer or other 
cancers. Subjects will be warned about these side effects and the physician will be alert to 
the earliest manifestations of thrombotic disorders including thrombophlebitis, 
cerebrovascular disorders, pulmonary embolism, and retinal thrombosis. If any of these 
occur or be suspected, the study medication will be discontinued immediately. 
We will also monitor women for less severe side effects such as cramps, breast 
tenderness, and breakthrough bleeding. 
Our research team includes a gynecologist, Dr. Aileen Gariepy, who has been involved in 
designing the current study and will provide expertise in progesterone treatment including 
monitoring adverse events. 
All potential risks and benefits of the study medication will be reviewed as part of the 
consent process, and will be assessed for at every check-in visit and when reminder 
phone calls by a research nurse or physician are made for appointments via study 
provided cell phones.  Study staff will query about possible side effects in an open-ended 
fashion that will allow us to elicit the most problematic side effects.  We will specifically ask 
about symptoms that would be indicative of thromboembolic events (swelling of the legs, 
shortness of breath, etc. and other known side effects (drowsiness)). All participants will 
receive standard TNP and some may find additional benefit from progesterone.  
Medical Monitoring: Potential participants will be carefully screened to rule out medical 
conditions that may increase the possibility of adverse events. Study participants will be 
carefully monitored by the study RA and a physician on the research team during each 
weekly visit. 
Participants will be withdrawn from the treatment arm of the study if they show severe 
psychological or symptomatic deterioration, unacceptable levels of adverse events as 
determined by the study physician, or if clinically necessary for ethical or safety purposes. 
Participants dropped from a study for these reasons or because they wish to withdraw from 
a study will be offered treatment as usual at the clinic or be referred to a higher level of care 
when appropriate. Private referral and/or hospitalization may also be offered according to 
the participants' needs and wishes.
Confidentiality will be protected by having records identified by code number only with the 
master list including names kept in a sealed envelope in a locked file in the Principal 
Investigator's office and by the pharmacy. Subjects will be given telephone numbers to call 
in case of emergency, 24 hours a day.   
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
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The risk associated with participating in this study is moderate, because progesterone 
treatment may be associated with mild side effects. Serious side effects associated with 
this treatment are not expected.
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? 
c.
Copy, paste, and then tailor an appropriate Data and Safety Monitoring Plan 
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal/moderate risk
iii. High risk
Moderate Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency, which must be 
conducted at a minimum of every 6 months (including when re-approval of the protocol is 
sought).  During the review process, the principal investigator (monitor) will evaluate whether 
the study should continue unchanged, require modification/amendment, or close to enrollment. 
Either the principal investigator, the IRB or NCI have the authority to stop or suspend the study 
or require modifications.
2. The risks associated with the current study are deemed greater than minimal for the 
following reasons: (choose those that apply)
We do not view the risks associated with the micronized progesterone as minimal risks.
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual or 
in advance of first-hand experience with the proposed study methods. Therefore, we provide a 
plan for monitoring the data and safety of the proposed study as follows:
Data and safety of patients will be monitored on a daily basis.  Dr. Yonkers will have the primary 
responsibility for monitoring data and adverse events.  Subjects will be seen by a study clinician 
at each visit.  The Project Director will review subjects' safety daily and will present subjects' 
clinical status and adverse experiences at the weekly Study Personnel meeting.  Entrance 
criteria of all subjects are reviewed at this meeting including results of self-report and other data 
collection measures.  Dr. Yonkers will oversee appropriate assessment and make a 
determination with regard to study discontinuation.  She will refer subjects who have had 
significant deterioration for further treatment but will follow them until they are connected with 
treatment.  Dr. Yonkers will ensure that information on subjects’ adverse effects are 
systematically collected and evaluated.
All serious AND unanticipated adverse effects which are deemed possibly, probably or definitely 
related will be reported to the Yale Human Research Protection Program, Internal Review Board 
(IRB) in compliance with University and Medical School research review boards’ protocols.  In 
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addition, the external Data and Safety Monitoring Board (see below) will be informed about any 
serious adverse effect, and their recommendation will be communicated to the IRB and NCI.  
We will report recruitment, follow-up and adverse events to this panel on a twice-yearly 
schedule.  Prior to study initiation, critical parameters for collection of side effects and for study 
discontinuation will be recommended to the DSMB who may use these or other measures to 
monitor safety of the ongoing trial.  
Data and Safety Monitoring Board (DSMB): This project will be monitored by a Data and 
Safety Monitoring Board (DSMB), because the study involves double-blind treatment of smokers 
with nicotine. This board is composed of persons not otherwise affiliated with the clinical study 
who are experienced in various aspects of the conduct of clinical trials for the treatment of 
addictive disorders. We propose three investigators located here in Connecticut who are not 
directly involved in this trial – Heather Lipkind, MD, Steve Bernstein, MD, and Hochang B. Lee, 
MD as the membership of the DSMB. These three clinicians have appropriate expertise in 
smoking cessation. None of these three are directly involved with this proposed trial and 
consequently should not pose a conflict of interest. 
We will report recruitment, follow-up, and adverse events to this panel on a quarterly fashion. 
Prior to study initiation, critical parameters for collection of side effects and for study 
discontinuation will be recommended to the DSMB who may use these or other measures to 
monitor safety of the ongoing trial. The DSMB will be available to convene outside of scheduled 
meetings, if necessary, due to concerns regarding a particular subject or due to any 
troublesome developments in subjects' experiences during the study. The DSMB will make 
appropriate recommendations for changes in the study protocol, if needed.  
This monitoring will be consistent with NIH policy regarding the protection of human subjects in 
research, and FDA guidance on practices for clinical trials (ICH E9) and good clinical practices 
(ICH E6). In general, the data to be reviewed will include screening data, baseline data, efficacy 
data, and safety data.  
In order for the DSMB to fulfill its mission of assuring the safety of human subjects and the 
scientific integrity of the studies conducted, the Board will have access to accumulating study 
outcome data in a manner that will protect its confidentiality and preserve its statistical integrity. 
The Board will examine accumulating data to assure that the risks and benefits of participation 
remain acceptable and that the results of the trial will be considered scientifically reliable. The 
conditions under which the Board will examine this data are described below. This monitoring 
will be consistent with NIH policy regarding the protection of human subjects in research, and 
FDA guidance on statistical practices for clinical trials (ICH E9) and good clinical practices (ICH 
E6). In general, the data to be reviewed will include screening data, baseline data, efficacy data, 
safety data, quality assurance data, accrual status including projections, total number of case 
report forms that are in-house, total number of case report forms that have been quality 
assured, times to milestones, FDA reports including annual IND reports, safety data from other 
sources for each clinical trial reviewed, and any other data that will help in the assessment of 
the effectiveness of the clinical trial.
The study will be monitored for safety in an ongoing way as well as twice each year formally by 
the DSMB.  The principal investigator will attend an initial part of this meeting to present the 
study’s adverse events and ongoing subject accrual, as well as any potential study design 
changes under consideration.  The remainder of the meeting will not include any direct study 
personnel until the end of the meeting, when the DSMB will convey directly to the principal 
investigator any safety or study conduct concerns, as well as requests for potential interim 
analyses.
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Following each DSMB meeting written minutes will prepared and distributed summarizing any 
recommendations. These written reports will insure timely communication with the study 
principal investigator with preparation of any protocol amendments necessary. After each DSMB 
meeting, this written report will describe all recommendations including additional safety steps. 
The FDA adverse drug experience reporting timelines will be utilized as timelines to disseminate 
feedback from the DSMB to the principal investigator and sub investigators. That is, three days 
for acute circumstances and ten days for non-acute circumstances. The recommendation of the 
DSMB will be communicated to the NCI Program Official.
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator, Kimberly Yonkers, MD, according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it 
results in any of the following outcomes:
1. Death;
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
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SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB-
approved protocol and informed consent document and (b) the characteristics of the 
subject population being studied; AND 
2. Is related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); AND
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known 
or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or 
non-medical in nature, and include – but are not limited to – serious, unexpected, and related 
adverse events and unanticipated adverse device effects.  Please note that adverse events are 
reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the 
prompt reporting requirements described in IRB Policy 710 should be reported to the IRB in 
summary form at the time of continuing review. If appropriate, such summary may be a simple 
brief statement that events have occurred at the expected frequency and level of severity as 
previously documented.  In lieu of a summary of external events, a current DSMB report can be 
submitted for research studies that are subject to oversight by a DSMB (or other monitoring 
entity that is monitoring the study on behalf of an industry sponsor).
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified (choose those that apply):
 All Co-Investigators listed on the protocol.
□ Yale Cancer Center Data and Safety Monitoring Committee (DSMC)
 National Institutes of Health
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□ Food and Drug Administration (Physician-Sponsored IND #_______)
□ Medical Research Foundation (Grant______)
□ Study Sponsor
□ Other Data Safety Monitoring Board (DSMB) or Committee (DSMC)
The principal investigator Kimberly Ann Yonkers MD, will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate the 
frequency and severity of the adverse events and determine if modifications to the protocol or 
consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
Main outcomes are prolonged smoking abstinence (Y/N at each point) and rates of 7-day 
point prevalence of abstinence(Y/N at each point). Following the recommendations of the 
Society for Research on Nicotine and Tobacco workgroup, the 7-day point prevalence is 
defined by self-reported smoking abstinence for the last 7 days, and expired carbon 
monoxide <10 ppm. Prolonged smoking abstinence is self-reported smoking abstinence 
starting with a 2-week grace period after the quit day (i.e., last 5 weeks of the treatment 
phase) without relapse to: the end of the trial, 1 month and 3 months post trial. Relapse is 
defined by a) smoked for 7 consecutive days or b) smoked at least once each week for 2 
consecutive weeks, or c) missed 2 consecutive weekly appointments or 2) failed breath test 
at any previous outcome assessment. Additional outcomes include measures of withdrawal 
(MNWS and QSU-B), and response inhibition (Stroop and SST).
Data Analysis:  We will follow CONSORT guidelines for the conduct and reporting of the 
trial. Descriptive statistics will be used to summarize the data on all randomized subjects, 
although, as per CONSORT, these parameters will not be included in the statistical model 
for primary analyses. Aim #1: To determine whether progesterone with TNP is superior to 
placebo and TNP we will use generalized estimating equations (GEE), an autoregressive 
correlation structure a binomial distribution and either identity or log link. A time-by-treatment 
interaction will be included in the GEE model.  The 8-week period will include a continuous 
version for the time variable and the follow up periods will treat time as categorical. A GEE 
model such as this can evaluate whether there is an overall difference between the 
progesterone and the placebo groups and whether the rate of change in smoking 
abstinence is different between the two groups.  For data that are missing, we will  perform 
inverse weighting to determine if data are missing at random (25). The weight will be the 
inverse of the probability not dropping out.  If there are concerns of informative dropout 
and/or informative intermittent missing data, which is typical of clinical trial data, we will use 
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pattern mixture models (26) and perform sensitivity analyses. In sensitivity analyses, 
participants who miss visits will be coded as smoking.  Exploratory analysis will include 
plasma estradiol and progesterone levels as covariates in order to determine if they 
contribute to treatment response and PANAS scores as mediators of response to 
progesterone or placebo.  Secondary analyses (the MNWS QSU-B) will be modelled 
similarly.  The main outcome measures for the Stroop test are throughput and interference 
score. For the SST, the main outcomes are stop signal reaction time (msec) and go reaction 
time (msec). We will use hierarchical linear models with each cognitive measure as separate 
longitudinal outcomes and treatment group assignment as regressors. 
Power: The sample size of 25 per condition was selected to provide an adequate 
assessment of feasibility and estimate effect sizes. Nonetheless, we determined what level 
of power we would have based upon a significance level of p<0.05, 2 sided test for 7-day or 
prolonged abstinence.  If rates of abstinence are 0.2 in the TNP only group and 0.4 in the 
progesterone and TNP group then the power would be 88%.  If the rate of abstinence in the 
treated group is 0.38, power is reduced to 80%.  In prior studies with the Stroop and SST, 
we found effect sizes >0.5 of progesterone vs placebo.  Our sample size would have adequate 
power (>80%) to detect a 2-fold difference in response. Clearly, these are large differences 
between groups but would provide a stable effect size estimate for a larger trial if findings 
are suggestive of a therapeutic effect of the combination treatment.
Timeline: We will use the first 3 months for study set up that will include final human 
subjects’ approval, hiring and training of staff, database set up, computerization of the 
interview and assessment measures.  Recruitment will begin immediately afterward. We will 
conduct ongoing data cleaning and will prepare reports for the human subjects’ board, the 
DSMB and NCI at regular intervals. The final analysis and study report will occur in the last 3 
months of the work period.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s). 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:  
a. What is the Investigational New Drug (IND) number assigned by the FDA? We will not be 
applying for an IND.
b. Who holds the IND? Multiple companies since the compound is generic.
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________
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For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies
 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.  X Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
      product. X Yes  
 No
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product. X Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). X Yes  
 No
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. X Yes  
 No
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
1) Progesterone: Progesterone, a natural hormone, is safe and well-tolerated by women. 
The safety, tolerability and efficacy of micronized progesterone is well established and it is 
FDA approved for hormone replacement therapy (HRT), absence of menstrual periods 
(amenorrhea), endometriosis, infertility treatment and preterm delivery. The recommended 
dose of progesterone for hormone replacement treatment is 200 to 400 mg/day, given as a 
single evening dose. After oral administration, micronized progesterone reaches its peak 
plasma levels in two to three hours and has an elimination half-life of three to four hours (18). 
Because of its short half-life progesterone will be given twice daily to maintain stable plasma 
levels. Progesterone doses higher than 400 mg/day will not be used since they are more likely 
to cause sedation. The safety and tolerability of micronized progesterone are well established. 
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Update June 2017: All participants had blood levels of progesterone drawn. We were blind to 
assignment of participants but at the end of the study found that those who were randomized to 
active progesterone had low progesterone levels. This could be due to the progesterone 
preparation or the fact that smokers metabolize it very quickly. In any case, the low 
progesterone levels in the active treatment group obviates our ability to test our hypothesis that 
progesterone augmentation assists abstinence for smokers. Given the lack of funds, we cannot 
repeat the project. Rather, we are recruiting a second cohort and are using a commercially 
available oral micronized progesterone rather than the previous medication that was 
compounded for the study. We plan to enroll a minimum of 12 people with an imbalanced ratio 
of 6 active to 1 placebo.
We will continue to obtain plasma levels of progesterone. This will enhance our ability to test 
our hypothesis. If need be in a final analysis, and give that this is a pilot project, we may be 
able to use the participants randomized to placebo in the first cohort and second cohort and the 
participants randomized to active in the second cohort.
2) Transdermal Nicotine Patch (TNP): TNP is currently available as an over the counter 
medication as an aid for smoking cessation. Consistent with the clinical guideline, participants 
who smoke more than 10 cigarettes per day will receive the following dose of TNP: 21mg/24 
hours for 4 weeks, 14mg for weeks 5 and 6 and 7 mg for weeks 7 and 8. Participants who 
smoke between 5-10 cigarettes per day will receive the following dose of TNP: 14mg/24 hours 
for 6 weeks, 7mg for weeks 7 and 8. Neither longer term (> 8 weeks) nor a higher dose (> 21 
mg/d) of nicotine patch improves efficacy over the standard treatment.  Adverse effects of TNP 
include skin irritation, nausea, vomiting, sweating, mood and sleep disturbances. To avoid skin 
irritation, participants will be instructed to place a new patch on a relatively hairless location, 
typically between the neck and waist at the start of each day and to rotate the site of application. 
Smokers who experience sleep disturbances will be instructed to remove the patch before 
bedtime. 
3. Source: a) Identify the source of the drug or biologic to be used. 
Banner Pharmacaps.  
b) Is the drug provided free of charge to subjects? 
 Yes  
 No
If yes, by whom? The medication is provided free of charge to the subjects, but is paid for by the 
grant supporting this research.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
Check applicable Investigational Drug Service utilized:
     
   YNHH IDS                                                                      
   Yale Cancer Center 
     
   CMHC Pharmacy                                                          
  West Haven VA
     
   PET Center                                                     
    None      
     
    Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
  
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As we have done with our previous studies, the oral micronized progesterone and placebo will be 
stored at room temperature in the locked medication cabinet at the PMS and Perinatal Research 
Program clinic. 
5. Use of Placebo: 
 Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a.
Describe the safety and efficacy of other available therapies. If there are no other
available therapies, state this.
All participants are receiving behavioral counseling and support as a first line treatment for 
relapse prevention.
b. State the maximum total length of time a participant may receive placebo while on the study. 
8 weeks
c.   Address the greatest potential harm that may come to a participant as a result of receiving    
  
   placebo. 
It is possible that subjects will relapse to smoking.  However, it is not known in receipt of the 
active medication could prevent such a risk.
d.   Describe the procedures that are in place to safeguard participants receiving placebo. 
Safety procedures are identical for all study subjects.  Most notably, all subjects are also 
receiving high-quality supportive counseling to teach relapse prevention skills.  Participants 
are seen for weekly visits with study physician and research nurse, and are at every visit 
evaluated for symptoms of depression, use of alcohol/cigarettes and illicit substances, safety 
risk towards themselves and others, and other comprehensive health checks.
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access. 
 
 No    If no, explain why this is acceptable.
We will not provide study drug after the study has ended because we do not know if it is helpful. 
 B.  DEVICES
1. Are there any investigational devices used or investigational procedures performed at YNHH, e.g., 
YNHH Operating Room or YNHH Heart and Vascular Center?  Yes 
  No 
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SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
  targeted for enrollment at Yale for this protocol_50__
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites_N/A__ 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards
X Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
  YCCI Recruitment database
 Clinicaltrials.gov Registry (do not send materials to HIC)
 Other (describe):
3.  Recruitment Procedures: 
a.
Describe how potential subjects will be identified.
We will recruit by direct screening from women attending regular care at the Women’s 
Center at the Yale New Haven Hospital York Street site, the Reproductive Health Clinic at 
Yale New Haven Hospital’s St. Raphael’s site and 1 Long Wharf, New Haven.  Women will 
be approached and we will ask them screening questions (if they smoke and how much, 
Fagerstrom scale, if they are interested in stopping smoking).  Women who meet the 
above smoking criteria and state that they would like to participate in a smoking cessation 
trial will be eligible for additional screening.  
We may also screen by media advertisement if above methods are inadequate.
b.
Describe how potential subjects are contacted. 
In clinic, potential subjects (i.e. patients arriving for regularly-scheduled care in the 
participating clinic) will be approached by trained research assistant personnel (yet to be 
hired).  If need be, we will also conduct mailings from commercially available mailing 
lists.  This will include a letter describing our study and providing a phone number and 
return envelope for people who are interested in participating.  We will contact women by 
phone and follow similar procedures.  A third method is by posters and brochures that 
will be placed in Obstetrician-Gynecologists offices.  This information will include our 
phone number for interested participants.  Flyers and brochures will be placed around 
the community and hospital websites for clinical trials.  This will also include call-back 
information.  Finally, we may place advertisements in print and electronic media.  People 
will be given call in information and we will return their phone calls.
c.
Who is recruiting potential subjects? 
Research Assistant, Virginia Otero-Santos has been hired and highly 
trained for this task. 
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4. Screening Procedures
a.
   Will a form be used to screen potential subjects for eligibility prior to the potential 
subject coming to the research office? 
 Yes  
 No
b.
 If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process. 
Women who are screened face-to-face, will be read a consent for screening script and 
those consenting will be asked if they smoke <5 cigarettes, are undergoing treatment 
for smoking, use illicit substances, are planning on moving out of the area within 6 
months or have irregular menstrual cycles.  Any yes response will indicate that they 
are not eligible and we will not retain any PHI.  Participants who are potentially eligible 
will undergo written consent and will be scheduled for an appointment that will include 
a full evaluation.
Possible participants who call in will be asked these questions and if they are not 
eligible will be thanked for their time.  No PHI will be retained.
Possible participants who call in and are potentially eligible will be read a consent for 
screening script about the study, will be asked eligibility questions and if potentially 
eligible and interested will undergo phone consent and offered an appointment.  The 
consent will be reviewed and signed during the subsequent face to face appointment.  
Any PHI (name, phone number and address) from possible participants who did not 
attend the appointment or were not provisionally eligible will be destroyed.  No 
additional information will be collected over the phone
HEALTH INFORMATION TO BE COLLECTED:
 
HIPAA identifiers: 
 Names (only for possible participants with a positive screen)
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000. (only for possible participants with a positive screen)
  Telephone numbers (only for possible participants with a positive screen)
 Fax numbers 
 E-mail addresses (only for possible participants with a positive screen)
 Social Security numbers 
Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
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5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
The YNHH Women’s Center and related St Raphael Chapel St site Women’s Clinic serve a 
large volume of patients from the greater New Haven area.  Patients in these clinics are quite 
loyal to the clinic and receive their healthcare there throughout the lifespan, from initial 
gynecological checkups, through pregnancy, and into menopause.  There is the possibility 
that some patients may know or be known to the Principal or Co-Investigator, although 
patients known to study providers will in no way be specifically recruited for this trial.
 No
If yes, describe the nature of this relationship.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) N/A
Choose one: For entire study: ______ For recruitment purposes only: _X_____
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
The brief pre-screening questions are minimal and PHI is collected only on 
participants for whom an appointment is scheduled.  For these individuals, the 
consent will be signed if screened in person or will be read to them over the phone.
We do not request subject’s authorization to use/disclose data if they are clearly not 
eligible in the brief pre-screening process because we will not collect or retain PHI.
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
The brief phone screen (smoked < 5 cigarettes, undergoing smoking treatment, irregular 
menstrual cycle) may be administered over the phone and it is not possible to obtain 
written signatures.  However, we will read the consent to possible participants who are 
scheduled for a complete screening visit.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
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Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent. 
Kimberly Ann Yonkers, MD
Ariadna Forray, MD
Marla Genova, MA
Heather Howell, MSW
Virginia Otero-Santos  
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 
Recruitment and Informed consent: The procedure for obtaining informed consent entails a face-
to-face discussion between the potential subject and a trained member of the research staff 
(research assistant, or study-related physician).  The entire protocol and all of its procedures and 
requirements, risks and potential benefits, are explained at length. To ensure that the respondent 
has the capacity to provide consent, the study personnel will ask women to summarize their 
understanding of the study. Additionally, women are encouraged to ask questions about any 
confusing points, and to consider carefully their choice to participate in this, or any, research 
protocol. Subjects are informed that they may withdraw from the project at any time, without 
prejudice, and without any effect on their medical care. 
Circumstances of consent: All subjects will be asked to provide consent at the study inception 
(any one who is preliminarily eligible on the brief pre-screen). All study data will be kept in a 
research chart or computer.  Computerized data are all encrypted.  Additional, a number identifier 
rather than subject name is used for computerized data.  Further, tables are separated from 
programs so there will be no way for people to associate data with responses of individuals. All 
subjects will be told through the informed consent process that if she develops suicidal or 
homicidal intent, this would incur assessment for voluntary or involuntary hospitalization, or a loss 
of some confidentiality. All subjects will be informed about the limits of confidentiality concerning 
suicidal intent or homicidal intent. Women who decline participation in the study will be given 
information on smoking cessation, informed of assets available from the CT Quitline, and referred 
for further treatment according to their clinic’s referral protocol. 
Of note: women may also be offered participation in other studies run by the same PI, based upon 
eligibility, at the time of screening.  The research staff would request permission from the subject 
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to contact her for other studies.  Women who decline this offer will be given information about the 
other study, and provided with a telephone number to call if she is interested.  
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
To ensure that the respondent has the capacity to provide consent, the study personnel will ask 
women to summarize their understanding of the study. Additionally, women are encouraged to 
ask questions about any confusing points, and to consider carefully their choice to participate in 
this, or any, research protocol. Subjects are informed that they may withdraw from the project at 
any time, without prejudice, and without any effect on their medical care.
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects. 
Compound authorization is attached for your review.
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use. 
All study procedures are available to English-speaking study subjects only.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
  Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
  Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes 
  No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity  
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  No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes 
  No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
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SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?   
Name, date of birth, address, telephone number, pap smear results, mental health and 
addictions questionnaires, general overview of medical history (including indicators related to 
inclusion/exclusion medical criteria) and measurements collected in the physical exam with 
the PI (ie weight, blood pressure, etc), results of urine laboratory tests (pregnancy “hcg” levels, 
presence of cotinine and/or drugs of abuse in the body, Serum Progesterone Level) and 
detailed information about use of cigarettes.       
       
b. How will the research data be collected, recorded and stored? 
Data will be collected on paper questionnaires and via computer interview.  Both documents 
are coded.
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
Patient identifying information is kept in a separate location from her data.  The two are linked 
by her study id number.  The key to this id code is kept in a separate location, accessible by 
study PI and Project Director.  Access to the code is limited to the PI and study Project 
Director and will be maintained until the study is completed and data analysis team determine 
that all data collection is complete and the dataset can be stripped of identifiers.  At such 
time, the code linking subject data to her name etc will be destroyed.
Do all portable devices contain encryption software? 
 Yes   
 No
         If no, see http://hipaa.yale.edu/guidance/policy.html
 
e.
What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
All HSPT and HIPAA guidelines are followed. Once a subject completes her study 
participation and data has been cleaned, her case-file is stripped of identifying information. 
De-identified data is kept onsite for 7 years while analysis and manuscripts are being 
prepared.
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data) 
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PI and research staff have access to PHI, for the purposes of conducting study-related 
procedures only. NCI has the right to view study records.
g.   If appropriate, has a Certificate of Confidentiality been obtained?
Yes, it has been obtained by NCI on January 6, 2016.  It expires on November 30, 2017.
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 
In the unlikely event that study personnel have reason to believe a child is in danger of neglect or 
abuse, the study consent form indicates that we will report this to DCF
SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
Participation in this study may be helpful to women to quit smoking. Every participant will 
receive evidence-based behavioral treatments for smoking cessation. The results of this study 
may lead to new treatments for smoking cessation in women.  Progesterone hormone has the 
potential to be such a treatment as it is safe and well-tolerated by women. Thus, if proven to be 
effective, the use of progesterone for smoking cessation in women is feasible.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
There are a myriad of evidenced-based treatment for nicotine cessation, and patients will be 
provided with such medical and community resources should they be eligible, but wish not to 
participate in our trial.  
2. Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation. 
There will be no cost to subjects for participating in this research protocol. 
 
 
 
 
 
Study medication and testing is 
provided free of charge.
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3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects. 
None 
4. In Case of Injury: This section is required for any research involving more than minimal risk.
Although injury is not expected, in the event that it occurs, treatment will be provided and the 
subject’s insurance will be responsible for payment. Subjects do not give up any legal rights by 
signing the study consent form.
a.
Will medical treatment be available if research-related injury occurs? Participants may be 
referred for treatment
b.     Where and from whom may treatment be obtained? They may seek treatment through 
their insurance or their current providers
c.     Are there any limits to the treatment being provided? They may receive any treatment 
their providers deem necessary.
d.     Who will pay for this treatment? They may use their personal insurance or personal 
funds
e.     How will the medical treatment be accessed by subjects? We will assist them in finding 
providers if they do not have providers
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Yonkers K, Forray A, Nich C, Carroll KM, Hine CE, Merry B, et al. Progesterone 
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Stein DG. Is progesterone a worthy candidate as a novel therapy for traumatic 
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9.
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Reeves D, Winter K, Kane R, Elsmore T, Bleiberg J. ANAM 2001 User's Manual. 
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Stead L, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine 
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Hammond CB. The Women's Health Initiative study: perspectives and 
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