Conditions: Nicotine Addiction Panic Attack
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: yes

Brief summary:
The purpose of the current study is to evaluate the efficacy of d-cycloserine in augmenting treatment of smoking cessation for individuals with panic attacks. The investigators hypothesize that individuals receiving DCS (versus those receiving placebo) will evidence greater smoking abstinence rates and decreased panic symptoms after receiving a combined CBT-based treatment for smokers with panic attacks.

Detailed description:

Arms:
arm 1: Individuals in this condition will receive 7 weeks of panic and smoking reduction treatment (PSRT) and one pill of d-cycloserine (DCS) one hour prior to sessions 3, 4, and 5 (i.e., 3 single doses). Participants will also be given nicotine replacement therapy as part of PSRT (i.e., the patch). arm 2: Individuals in this condition will receive 7 weeks of panic and smoking reduction treatment (PSRT) and one pill placebo dose one hour prior to sessions 3, 4, and 5 (i.e., 3 single doses). Participants will also be given nicotine replacement therapy as part of PSRT (i.e., the patch).

Interventions: intervention 1: d-cycloserine intervention 2: Pill Placebo intervention 3: Nicotine replacement therapy intervention 4: Panic and Smoking Reduction Treatment
Intervention descriptions: intervention 1: d-cycloserine is a medication thought to be associated with fear extinction. intervention 2: None intervention 3: All participants will receive Nicoderm CQ®, 24-hour transdermal nicotine patches and will be educated about the use of the patch at the session immediately prior to quit date. They will be instructed to apply one patch daily, beginning on quit date (week 5). Participants will use the 3-step tapering Nicoderm process (21-mg, 14-mg, and 7-mg). This regimen has been used in previous trials with a similar formulation of the patch (Fiore, 2000). A meta-analysis found no differences in outcome between 16- or 24-hour patches (Fiore et al., 1994). Participants who continue to smoke or lapse after quit day will not be instructed to discontinue the patch until their smoking level reaches 4 cigarettes/day for 4 days. Smokers who lapse during treatment will be encouraged to set a new quit date and continue their cessation attempt. intervention 4: PSRT incorporates elements of standard smoking cessation treatment (i.e., counseling plus NRT) with procedures for reducing panic and enhancing tolerance to withdrawal sensations. Written therapist and patient manuals will be used and followed at all times to ensure standardized delivery of the treatment. Interventions that uniquely focus on addressing panic, fears and intolerance of anxiety, bodily-related sensations, and affect-relevant withdrawal symptoms include: (1) interoceptive exposure; (2) corrective information about anxiety and cognitive interventions designed to teach patients alternatives to catastrophic misinterpretations of the sensations and their feared consequences; and (3) situational exposure.

Protocol document:
Prot_000.pdf: 
Research Proposal 
 
 
 
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Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine 
NCT01944423 
Last Revised: 6/7/17 
 
 


Research Proposal 
 
 
 
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Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
1. TITLE 
 
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine 
2. PRINCIPAL INVESTIGATORS 
 
Jasper Smits, Ph.D.  
smitsja1 
Department of Psychology 
Michael Otto, Ph.D. 
Department of Psychology 
Boston University 
 
Michael Zvolensky 
Department of Psychology 
University of Houston 
 
3. PURPOSE 
 
Approximately 9-15 million smokers in the U.S. meet criteria for at least one anxiety disorder during their lifetime 
(Kessler et al., 2005), and these individuals experience significant challenges quitting tobacco (Piper et al., 2010; 
Zvolensky et al., 2008). Yet, little attention has been given to the maintenance of tobacco use among persons with 
anxiety disorders, and in particular, smokers with a history of panic attacks. This group is especially important to study 
because research shows that they have significantly lower quit rates than smokers with no history of panic attacks, and 
that they respond the same to placebo, single cessation pharmacotherapy, and combination cessation pharmacotherapy 
(Piper et al., 2010a). Recent efforts from our group have led to the development of a cognitive-behavioral program, 
Panic and Smoking Reduction Treatment (PSRT), which integrates interoceptive exposure, cognitive restructuring, and 
psychoeducation exercises with standard smoking cessation strategies and nicotine replacement therapy. Early testing 
of this program indicates that this targeted smoking cessation treatment for smokers with panic attacks is efficacious, 
but leaves room for improvement. Specifically, a study examining the efficacy of PSRT revealed that individuals receiving 
PSRT evidenced significantly greater reductions in anxiety sensitivity and were more likely to be smoke free than those 
receiving standard smoking cessation treatment (Zvolensky et al., 2008). However, only 42.7% of the PSRT condition 
were smoke-free at 16 weeks post-quit.  
 
The current study seeks to evaluate whether d-cycloserine (DCS) can augment the efficacy of PSRT. DCS is a partial 
NMDA agonist, which has shown to enhance the retention of fear extinction (Davis et al., 2005; Richardson et al., 2004; 
Ledgerwood et al., 2004; Ledgerwood et al., 2005), which is a key mechanism underlying the efficacy of PSRT (Zvolensky 
et al., 2008). Of note, DCS has shown to be an effective and safe augmentative strategy in panic disorder (Otto et al., 
2010), which may make it a particularly effective strategy for smokers with panic attacks.  
 
Our study consists of three aims: to compare, in a randomized clinical trial, (1) the effects of PSRT+DCS versus PSRT+PBO 
on smoking cessation outcomes and (2) the effect of PSRT+DCS vs. PSRT+PBO on the frequency and intensity of panic 
attacks, withdrawal symptoms, negative affect, anxiety sensitivity, and distress intolerance; and (3) to explore the 


Research Proposal 
 
 
 
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Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
mechanisms by which PSRT+DCS improves smoking cessation outcomes. We hypothesize that individuals in the 
PSRT+DCS condition will evidence superior smoking cessation outcomes (i.e., longer time to first smoking lapse and 
relapse and lower PPA) and reduced anxiety and panic symptomatology compared to those in the PSRT+PBO condition.  
 
To achieve our aims, adult smokers with panic attacks from the Austin community will be randomly assigned to either: 
(1) PSRT+DCS or (2) PSRT+PBO. Primary outcome measures will be point prevalence abstinence (PPA), time to first 
smoking lapse, and time to smoking relapse. Proposed mediators include panic attacks, distress intolerance, anxiety 
sensitivity, nicotine withdrawal symptoms, and negative affect. These variables will be assessed at baseline, weekly 
during the treatment phase, and at 2, 4, 8, 10, 16, and 24 weeks after quit date.  
 
The proposed study represents a crucial and important stage in translating basic research to strategies for treating 
nicotine dependence. The investigation addresses an important public health issue by testing an integrated intervention 
- informed by basic research - that may lead to a more effective and efficient treatment for at-risk smokers while 
simultaneously isolating explanatory mechanisms. The expected findings should: (1) guide advances in the theoretical 
conceptualization of the mechanisms involved in panic- and anxiety-smoking relations; and (2) provide initial effect size 
data for the addition of DCS to an integrated psychosocial/behavioral and pharmacological smoking cessation 
intervention for smokers with panic attacks, and thus provide the necessary data for a large-scale follow-up trial. 
 
Participants will also complete a computerized facial recognition task that examines generalization of memory to 
emotional stimuli. In the context of learning about threats, generalization can be adaptive; however, when the threat 
response is overgeneralized, it can be impairing. Recent research has focused on fear overgeneralization as a potential 
transdiagnostic mechanism of anxiety disorders (for review see Dymond et al., 2015; Lissek & Grillon, 2015). This 
research utilizes Pavlovian conditioning paradigms that pair one stimulus (CS+) with an aversive event (e.g., shock), and 
subsequently examines how defensive responses (e.g., startle, risk assessment) are generalized to stimuli that resemble 
the CS+. This line of research finds some degree of generalization in healthy participants (Lissek et al., 2008), but 
overgeneralization in patients with panic disorder (Lissek et al., 2010), generalized anxiety disorder (Lissek et al., 2014), 
posttraumatic stress disorder (Levy-Gigi et al., 2015), and obsessive compulsive disorder (Kaczkurkin et al., 2013). Thus, 
overgeneralization represents a potential treatment target (Kheirbek et al., 2012). This task aims to expand the 
understanding of stimulus generalization by focusing on recognition (i.e., no use of shock or Pavlovian conditioning) of 
socially relevant stimuli (i.e., faces), which may underlie the generalization of emotional responses observed in 
conditioning paradigms.  
 
4. PROCEDURES 
The proposed study will utilize a prospective, experimental research design. We will recruit adult daily smokers with a 
history of panic attacks in the last year and they will be randomly assigned to either: (1) Panic and Smoking Reduction 
Treatment plus d-cycloserine (PSRT+DCS) or Panic and Smoking Reduction Treatment plus placebo (PSRT+PBO). 
Participants will be adults between the ages of 18-65 who have smoked daily for at least a year, currently smoke an 
average of at least 8 cigarettes per day, and report a motivation to quit smoking in the next month of at least 5 on a 10-
point scale. Moreover, participants will have elevated fears of withdrawal and anxiety related bodily sensations and a 
tendency to regulate these feelings with smoking, as indexed by meeting or exceeding established cut-off scores on the 
Smoking Abstinence Expectancies Questionnaire (≥78), respectively. Eligible participants will be randomly assigned to 
either condition by the project biostatistician (David Rosenfield, Ph.D. – Consultant at Southern Methodist University). 
Primary outcome measures will be point prevalence abstinence (PPA), time to first smoking lapse, and time to smoking 


Research Proposal 
 
 
 
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relapse. Proposed mediators include panic attacks, distress intolerance, anxiety sensitivity, nicotine withdrawal 
symptoms, and negative affect. These variables will be assessed at baseline, weekly during the treatment phase, and at 
2, 4, 8, 10, 16, and 24 weeks after quit date. 
 
Eligibility Screening 
Internet and Telephone Prescreen & In-person or Telephone Screening. Individuals interested in participating in the 
study will be directed via various recruitment strategies to an Internet prescreen using REDCap. The first page of the 
prescreen survey will include the consent form for the prescreen survey, telephone screening, and demographic and 
medical history questionnaire procedures where participants will be able to give informed consent through REDCap. This 
online prescreen will assess basic eligibility criteria and individuals who appear potentially eligible will be further 
assessed via a telephone prescreen. The prescreen procedure is the first point of contact for participants, and it will 
allow us to ask critical information about the potential participant’s willingness and ability to commit to the frequency of 
clinic visits as well as the assessment of inclusion criteria. Participants will also be asked during the phone screen 
whether they have sufficient command of the English language, as visits will be conducted in English and all self-report 
measures are in English. If a participant passes the Internet and Telephone Prescreen, they will complete the Screening 
assessment either over the phone or asked to come into the lab for an in-person screening. The screening will include a 
psychiatric evaluation process through the Structured Clinical Interview for DSM-IV (SCID) and the Panic Disorder 
Severity Scale (PDSS) to evaluate the presence of panic attack history and psychiatric exclusion criteria. The interview 
will also allow for assessment of primary and secondary diagnoses if applicable. Suicidality will also be assessed at this 
time using the Columbia-Suicide Severity Rating Scale (C-SSRS). Demographic and general medical health history 
information will also be captured during the screening assessment. If a participant is assessed over the phone, the 
demographic and general medical health history survey will be sent to them via REDCap.  
In-Person Screening Assessment. If a participant comes into the lab for their screening assessment, they will first read 
and give signed, informed consent. The researcher will answer any questions they may have and complete the 
screening. Participants’ blood pressure, heart rate, and CO2 will be measured at this visit.  
Medical Screening. A study physician (Dr. Carlos Tirado) will review the patient’s medical history to determine if it will 
be safe for them to take the study medication. The physician will schedule appointments and order lab tests if he deems 
it necessary should the patient be present with any of the following conditions: 1. Urinary complaints (flank pain, pyuria, 
dysuria) 2. Fever greater than 101.4 F/38.5 C within the last 24 hours 3. Diabetes 4. History of hypo/hyper thyroidism 5. 
Known hepatic disease (viral hepatitis, alcoholism) 6. Known or suspected substance abuse 7. Fatigue (acute) 8. Weight 
loss greater than 10 pounds in last 30 days 9. Other physical exam and medical history finding that in the physician's 
judgment requires further laboratory assessment to rule out a significant medical condition. If deemed necessary by Dr. 
Tirado, safety evaluations will also include laboratory tests (CBC, chemistry profile, thyroid function test, and urinalysis). 
A urine pregnancy test will be performed on all female participants of childbearing potential at intake and monthly 
following randomization. Research personnel will also discuss the potential side effects of DCS with potential 
participants.  Any positive pregnancy tests resulting in exclusion from the study will be handled by having the PI or 
physician meet with the participant to provide a feedback session. 


Research Proposal 
 
 
 
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Baseline Visit for participants that completed the Screening Assessment over the phone 
The consent form will be sent to participants via REDCap before the appointment so that they have time to read through 
the form and give their informed consent. Upon arrival, if the participant has not signed the consent form, they will 
receive an informed consent form explaining the details of the study, potential benefits and risks of participation, and 
the procedures they will undergo if they choose to participate. After reading the informed consent document, a study 
coordinator will discuss these issues with the potential participant and will answer any questions he or she may have 
about the study and participation. If the individual chooses to sign the informed consent, he or she will have their blood 
pressure, heart rate, and CO2 measured. Those who have readings outside of the safe range (ranges are provided by our 
study physician: 85mmHg < Systolic BP < 160mmHg and 55mmHg < Diastolic BP < 100mmHg) will have their 
measurements sent to our study physician for further safety assessments. If the physician deems it is unsafe for the 
participant to take the study medication, they will be notified, thanked for their time, and dropped from the study. All 
participants will continue with the rest of the baseline visit which includes introduction to the research study, goals of 
the treatment, explanation of data collection documents, and assignments including surveys to be completed before 
coming to the lab. Participants will also be asked to provide contact information of two significant others we can reach 
out to if we loose contact with them. If we need to contact these significant others, we will let them know the 
participant gave us their information, if they can provide us with the participant’s new contact information (if it has 
changed, and/or leave them a message asking to contact us.          
 
Randomization  
The project Biostatistician, Dr. David Rosenfield, will oversee the randomization to either PSRT+DCS or PSRT+PBO 
conditions. Both participants and study personnel will be blind to study condition, and study medication will be labeled 
by either “A” or “B” by the pharmacy in order to blind the medication administration. A random number generator will 
be used to assign individuals to either condition. Only Dr. Rosenfield will have the information necessary to break the 
blind. Prior to data analyses, Dr. Rosenfield will check the balance of randomization and control for any factors that are 
imbalanced.  
Intervention Modules 
Panic Smoking Reduction Treatment (PSRT). Table 1 provides a session-by-session outline and illustrates the integrated 
nature of this hybrid treatment as well the nature of the experimental manipulation (i.e., DCS vs. PBO). PSRT 
incorporates elements of standard smoking cessation treatment (i.e., counseling plus NRT) with procedures for reducing 
panic and enhancing tolerance to withdrawal sensations. Written therapist and patient manuals will be used and 
followed at all times to ensure standardized delivery of the treatment (7-weeks of individual therapy). Interventions that 
uniquely focus on addressing panic, fears and intolerance of anxiety, bodily-related sensations, and affect-relevant 
withdrawal symptoms include: (1) interoceptive exposure; (2) corrective information about anxiety and cognitive 
interventions designed to teach patients alternatives to catastrophic misinterpretations of the sensations and their 


Research Proposal 
 
 
 
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feared consequences; and (3) situational exposure. Particularly novel here is that we are asking patients to remain 
cigarette-free prior to certain sessions before to the quit date. Indeed, this allows for direct extinction training during 
the session (where emotional cues are induced and no smoking occurs), and because patients can remain smoke-free for 
hours after the session (i.e., 2 to 12 hours after PSRT; Zvolensky et al., 2008), this training can ensure absence of a 
contingency between emotional induction and cigarette use, and during the time of DCS use. Lastly, the therapist will 
schedule with the participant a regular time each week between quit date (week 5) and the end of the protocol (week 
29) to meet via telephone. During these brief telephone meetings, the therapist will address any barriers that may arise 
and to ensure that participants abstain from smoking. The therapist will provide social support, trouble shoot for high-
risk situations, and develop a plan to keep the participant on track with study goals.  
 
1.  Table Session-by-session outline of intervention procedures 
DCS/PBO 
Administration 
Week 
Standard Smoking Cessation Procedures 
Panic Reduction Procedures 
 
1 
• 
Provide quit support and 
reinforcement 
• 
Discuss past experiences 
• 
Set quit date (Monday of Week 5) 
• 
Initiate self-monitoring (tracking 
smoking and noting cues for 
smoking) 
• 
Integrated treatment (PSRT) 
rationale 
• 
Education on panic-smoking link 
• 
Interoceptive exposure 
introduction 
• 
Interoceptive exposure practice 
• 
IE homework practice assigned 
 
• 
No 
2 
• 
Help identify high-risk for relapse 
situations 
• 
Discuss abstinence violation effect 
• 
Develop coping strategies 
• 
Encourage enlisting social support 
• 
Provide self-help materials 
 
• 
Review education on panic-
smoking link 
• 
Review interoceptive exposure 
rationale 
• 
Cognitive restructuring 
• 
IE practice 
• 
IE homework practice assigned 
• 
Instruction to refrain from smoking 
4 hours prior to Session 3 
 
• 
No 
3 
• 
Review elements discussed in 
Session 2 and isolate any areas of 
question/concern for patients 
• 
Interoceptive exposure practice 
• 
Cognitive restructuring  
• 
IE homework practice assigned 
• 
Instruction to refrain from smoking 
4 hours prior to Session 4 
 
• 
Yes 
4 
• 
Discussion of upcoming quit day 
• 
Instruct on proper use of NRT 
• 
Homework practice review 
• 
Interoceptive exposure practice 
• 
Cognitive restructuring  
• 
IE homework practice assigned 
• 
Yes 
5 
QUIT WEEK 
• 
Initiate NRT 
• 
Discussion of quitting experiences 
• 
Provide support 
• 
Encourage self-awareness of the 
role of panic-related experiences 
in smoking behavior and urge to 
smoke.  
• 
Yes 


Research Proposal 
 
 
 
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• 
Anticipate high-risk situations 
• 
Underscore importance of 
integrating exposure, non-
catastrophic thinking, and 
education to maintain abstinence.  
• 
Cognitive restructuring  
• 
Interoceptive exposure 
6-7 
• 
Continue NRT 
• 
Provide support 
• 
Anticipate high-risk situations 
• 
Develop social support for 
nonsmoking 
• 
Lifestyle changes (e.g., stress 
management, healthy diet, exercise, 
and increasing pleasant nonsmoking 
activities) 
• 
Cognitive restructuring 
• 
Interoceptive exposure 
• 
Situational exposure (i.e., avoided 
situations) 
• 
No 
 
Nicotine Replacement Therapy (NRT). All participants will receive Nicoderm CQ®, 24-hour transdermal nicotine patches 
and will be educated about the use of the patch at the session immediately prior to quit date. They will be instructed to 
apply one patch daily, beginning on quit date (week 5). Participants will use the 3-step tapering Nicoderm process (21-
mg, 14-mg, and 7-mg). This regimen has been used in previous trials with a similar formulation of the patch (Fiore, 
2000). A meta-analysis found no differences in outcome between 16- or 24-hour patches (Fiore et al., 1994). Participants 
who continue to smoke or lapse after quit day will not be instructed to discontinue the patch until their smoking level 
reaches 4 cigarettes/day for 4 days. Smokers who lapse during treatment will be encouraged to set a new quit date and 
continue their cessation attempt.  
D-cycloserine or Placebo Treatment. All capsules will be identical in appearance to maintain the blind design of the 
study. Study capsules will be prepared containing: (a) 250mg d-cycloserine or (b) pill placebo. Individual doses of study 
medications, prescribed by Dr. Tirado, will to be dispensed to patients by study personnel 1 hour prior to sessions 3-5 
and patients will be asked to remain in the clinic until session time. Because all pill taking is observed, no pill counts are 
necessary to help ensure adherence to the randomized drug condition. All medications will be stored in a locked 
refrigerator. 
 
A. LOCATION 
All data will be collected at the University of Texas at Austin. Upon completion of data collection, data analysis will take 
place at UT, Southern Methodist University (PI: David Rosenfield), the University of Houston (PI: Michael Zvolensky), and 
Boston University (PI: Michael Otto). All data will be encrypted with numeric codes so that no identifying information 
will be included in analyses. Drs. Rosenfield, Zvolensky and Otto will obtain IRB approval from their respective 
instructions prior to accessing the data. 
B. RESOURCES 
The project is funded through the National Institute on Drug Abuse (NIDA) grant number R34DA034658.  


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C. STUDY TIMELINE  
Data collection will begin upon IRB approval (tentatively, November of 2013) and has an anticipated end date of August 
2017. Data will be analyzed soon after data collection ends and the project will end once the findings has been 
published. We anticipate to keep the study open until December 2018.  
 
5. MEASURES 
Assessment Instruments 
Screening Measures   
Eligibility Screen. This prescreen questionnaire and telephone-screening will assess inclusion and exclusion criteria.  
Motivation to Quit Smoking. This 10-item measure will be used to determine participants’ pre-cessation motivation to 
quit smoking (Rundmo et al., 1997). 
Demographics. Participants will be asked to provide standard demographic information (i.e. age, gender, race/ethnicity, 
level of education, etc.) as well as history of medical problems. 
Psychiatric History. Diagnostic exclusions and lifetime prevalence of Axis I diagnoses will be determined by the 
Structured Clinical Interview for DSM-IV (SCID-NP; First et al., 2007) during the screening. The diagnostic interview will 
be administered by trained research personnel and will be supervised by the PIs. This interview will serve to 
contextualize participants’ psychiatric history at baseline. In addition, the SCID will be conducted at the final follow-up 
visit (week 29) in order to assess for changes in diagnoses. Anxiety sensitivity interventions have been shown to aid in 
the prevention of future mental health disorders, so assessing for changes in diagnostic status in this population will be a 
useful addition to the literature.  
Suicide. The Columbia Suicide Severity Rating Scale (C-SSRS; Posner, Oquendo, Gould, et al. 2007) is a standardized 
measure of current and past self-injurious behavior, suicidal intent, and suicidal behaviors. The C-SSRS has demonstrated 
good reliability and validity (Hammad et al., 2006; Posner et al., 2007). The C-SSRS will be administered as part of the 
diagnostic interview in order to assess for a history of suicide attempts or current suicidal thoughts or plans. 
Vital Signs. As part of their screening visit, participants’ blood pressure will be assessed.  
Laboratory Testing. A study physician will review the patient’s medical history and conduct a complete physical 
examination if deemed necessary. Safety evaluations will also include laboratory tests (CBC, chemistry profile, and 
thyroid function test). A urine pregnancy test will be performed as part of the general physical medical evaluation of 
patients during the baseline visit and to assess for study exclusion criteria. In addition, a urine pregnancy test will be 
performed each month following randomization. Blood draws will be performed(if deemed necessary) in our laboratory 


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at the University of Texas by a certified phlebotomist and Clinical Pathology Laboratories in Austin will analyze the 
samples. 
Measures of smoking behavior, nicotine dependence, and withdrawal symptoms 
 
 
Smoking History Questionnaire (SHQ). Smoking history and pattern will be assessed with the SHQ, a 30-item measure 
that includes items pertaining to smoking rate, age of onset of initiation, years of being a regular smoker, etc. (Brown et 
al., 2002; Zvolensky et al., 2005). This measure will serve to contextualize the participants’ smoking behavior and history 
at intake. 
Fagerström Test for Nicotine Dependence (FTND). The FTND is a 6-item scale designed to assess gradations in tobacco 
dependence (Heatherton et al., 1991). This measure will serve to quantify nicotine dependence, which will be used as a 
covariate in the primary analyses. 
Nicotine Withdrawal Symptoms. Given its potential relation to outcome, we will monitor withdrawal severity at 
baseline, weekly throughout treatment and at follow-up assessments, using the Minnesota Withdrawal Scale, a reliable 
and sensitive 10-item scale (Hughes & Hatsukami, 1986).  
Questionnaire of Smoking Urges (QSU). The QSU is a 10-item measure that assesses urges and cravings for cigarettes 
(Cox et al., 2001). We will monitor craving at baseline, weekly throughout treatment, and at the follow-up assessments. 
This assessment of urges can be used to evaluate consistency (or lack thereof) with withdrawal symptoms in follow-up 
tests from the data set.  
Smoking Abstinence Expectancies Questionnaire (SAEQ). The SAEQ is a 28-item measure that assesses short-term 
psychological and physiological consequences to (hypothetically) abstaining from smoking among those that smoke 
everyday. The measure has 4 internally consistent subscales: Negative Mood, Somatic Symptoms, Harmful 
Consequences, and Positive Consequences.  
Smoking Cessation Self-Efficacy (SE). A participant's confidence that he or she can carry out a behavior such as quitting 
smoking will be measured at baseline using a well-established 9-item scale developed by Velicer, Diclemente, Rossi, and 
Prochaska (1990). This instrument includes a subscale regarding confidence in remaining abstinent in negative affect. In 
previous work, we have successfully used this negative affect subscale for smoking self-efficacy (alpha = .85; Zvolensky, 
Schmidt et al., 2003). 
Smoking Cue Appeal Survey (SCAS). The Smoking Cue Appeal Survey (Murray, McHugh, Rowley, Sirota, & Otto, 2010) 
measures cue appeal to sensory smoking cues. An initial study demonstrated good psychometric properties associated 
with smoking status and craving (Murray et al., 2010). 
Barriers to Cessation Scale (BCS). The Barriers to Cessation Scale (Macnee &  Talsma, 1995) is a 19-item measure assessing 
barriers or specific stressors associated with smoking cessation. It has been found to have good internal consistency, good 
content, and predictive validity (Macnee & Talsma, 1995). 


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Smoking Consequences Questionnaire – Brief (SCQ-Brief). The SCQ-Brief is an abbreviated version combining both the 
Smoking Consequences Questionnaire (SCQ; Brandon & Baker, 1991), an 80-item measure assessing positive and negative 
smoking outcome expectancies, and the Smoking Consequences Questionnaire - Adult (SCQ-A; Copeland et al., 1995), a 
55-item measure considered to be more suitable for adults. The brief version is a 25-item measure that has shown good 
internal consistency and convergent validity (Rash & Copeland, 2008). 
Intolerance for Smoking Abstinence Discomfort (IDQ-Smoking). The IDQ-Smoking questionnaire is a 17-item measure that 
assesses the intolerance of discomfort associated with recent smoking cessation. The IDQ-S has three reliable 
components: withdrawal Intolerance, Lack of Cognitive Coping, and Pain Intolerance. 
Smoking Status. Self-reports of smoking status will be collected from participants at baseline, weekly throughout 
treatment and at follow-up assessments. Participant reports of abstinence at all times will be verified by expired carbon 
monoxide, and additionally at the 8, 10, 16, and 24-week interviews with saliva cotinine (see Table 2). The main outcome 
analyses are based upon 7-day point prevalence abstinence (i.e., reported abstinence of at least 7 days prior to each 
scheduled follow-up). Self-report will be overridden by objective verification in the conservative direction (Proceedings of 
the National Working Conference on Smoking Relapse, 1986). 
In addition to point-prevalence outcomes, we also will use the timeline follow-back (TLFB) procedure for assessing the 
time to first smoking lapse and the time to first relapse, defined as the 7th day on which smoking occurs. The TLFB 
procedure has demonstrated good reliability and validity (Sobell & Sobell, 1996). The TLFB will be administered at each 
follow-up to assess cigarette use since the previous assessment.   
Biochemical Verification. Self-reported abstinence at the 8, 10, 16, and 24-week follow-ups will be verified by saliva 
cotinine (cutoff value of 10 mg/ml) for stated abstinence of 2 weeks or more (cotinine may be incompletely metabolized 
before this time), and carbon monoxide analysis of breath samples (8ppm cutoff) for stated abstinence of 24 hours to 2 
weeks (Jarvis et al., 1987). Saliva samples will be frozen and analyzed by an outside laboratory for cotinine level using 
radioimmune assay. Expired air carbon monoxide levels will be assessed with a Vitalograph Breathco carbon monoxide 
monitor (Jarvis et al., 1987). Detected values above the stated cutoff scores will be considered indicative of smoking. 
Mood, Emotion, and Cognition 
Inventory of Depression and Anxiety Symptoms (IDAS). The IDAS is a 64-item measure assessing specific symptom 
dimensions of major depression and related anxiety disorders (Watson et al., 2007). The scales are internally consistent 
and show excellent convergent validity and good discriminant validity (Watson et al., 2007).  
Difficulties with Emotion Regulation Scale (DERS). The DERS is a 36-item self-report measure of clinically-relevant 
difficulties in emotion regulation (Gratz & Roemer, 2004). The scale has been validated in cocaine dependent (Fox et al., 
2007) and alcohol dependent (Fox, Hong, & Sinha, 2008) populations. 


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NEO Five-Factor Inventory (NEO-FFI). The NEO-FFI is a 60-item self-report measure of five basic personality factors (Costa 
& McCrae, 1989). The measure has been shown to have high test-retest reliability (Robins et al., 2001) and internal 
consistency (Costa & McCrae, 1992). 
 Regulatory Focus Questionnaire (RFQ). The Regulatory Focus Questionnaire (RFQ; Higgins et al., 2001) was derived from 
a factor analysis of items assessing the history of individuals’ success at promotion and prevention tasks over the course 
of their lives. 
Sleep, Financial Strain, Life Stressors  
Financial Strain Questionnaire (FINSTR). The Financial Strain Questionnaire (Perlin et al., 1981) is a measure of financial 
strain with 8 items (e.g., “Do you have enough money for the kind of clothing you and your family should have?”).  
Impulsivity 
Delay Discounting. The Delay Discounting Task adapted from Kirby and Marakovic (1996) evaluates the degree to which 
participants are willing to delay rewards. Participants answer questions that evaluate choice points relative to delaying 
cash rewards (e.g., Would you rather have $10 in 30 days or $2 at the end of the session). Participants will be informed 
to make their choice as if they were to receive the amount they chose, but that they will not receive additional 
compensation as part of the study. 
UPPS. The UPPS Impulsive Behavior Scale is a 44-item self-report measure of four personality factors hypothesized to 
underlie impulsive behaviors: sensation seeking, (lack of) premeditation, (lack of) perseverance, and urgency.  The 
measure has demonstrated strong internal consistency reliability for each of the four subscales and has been linked to 
self-report of risky behaviors (e.g., Whiteside & Lynam, 2003; Whiteside, Lynam, Miller, & Reynolds, 2005).  We will use 
the UPPS-P, a variant of this measure that includes 15 additional items designed to assess positive urgency in addition to 
negative urgency (Cyders et al. 2007). 
Measure of panic severity 
Panic Attack Questionnaire (PAQ). The Panic Attack Questionnaire (PAQ) is a commonly-used self-report measure to 
assess panic attacks. It begins by providing respondents with a definition of panic attacks (according to DSM-III) to create 
a common understanding of the construct. From there, participants construct their self-assessment. It collects 
information about participant's frequency of panic attacks and the context in which they arose, as well as intensity of 
pain symptoms. The final section of the questionnaire consists of open-ended questions about medication use, stress, 
and treatment received for other illnesses or disorders. 
Panic Disorder Severity Scale. The Panic Disorder Severity Scale (PDSS; Shear et al., 1997) is a 7-item, psychometrically-
sound clinician-rated instrument for measuring indices of panic severity, including a) frequency of panic attacks, b) 
distress during panic attacks, c) anticipatory anxiety, d) agoraphobic fear and avoidance, e) interoceptive fear and 
avoidance, f) impairment of work functioning, and g) impairment of social functioning. Items are rated on a five-point 


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The University of Texas at Austin                                                                                                          Page 12 of 29  
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Likert scale (ranging from 0 [none] to 4 [extreme]) with a total possible score of 28. In the present study, we are 
employing the PDSS global composite as an index of panic attack severity. Individual items can theoretically be 
employed in follow-up tests from this same measure (Shear et al., 1997), making it an ideal choice for the current study. 
Measures of anxiety sensitivity, distress intolerance, and negative affect 
Anxiety Sensitivity Index-III (ASI-III). The ASI-III is a 18-item psychometrically-sound measure of AS whereby participants 
rate their fear of internal anxiety-related sensations (Taylor et al., 2007). 
Distress Intolerance Index (DII). The DII (McHugh & Otto, 2010) is a 10-item self-report measure of an individual’s 
perceived ability to tolerate distressing states. This measure was developed in the context of a factor analysis of the 
most commonly applied measures of distress intolerance, namely the Anxiety Sensitivity Index (Peterson & Reiss, 1992), 
Distress Tolerance Scale (Simons & Gaher, 2005), and Frustration Discomfort Scale (Harrington, 2005). 
 
Positive and Negative Affect Schedule (PANAS). The PANAS is a 20-item psychometrically-sound mood measure that 
assesses two global dimensions of affect: positive and negative (Watson et al., 1988).  
Brief Pain Inventory (BPI). The BPI short form is a 15-item measure often used in clinical trials. The BPI allows patients to 
rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and 
function. Initially developed to assess pain related to cancer, the BPI has been shown to be an appropriate measure for 
pain caused by a wide range of clinical conditions. It is now one of the most widely used measurement tools for 
assessing clinical pain.   
Measures of treatment integrity, safety, and acceptance 
Vital Signs. As part of their screening visit, participants’ blood pressure and heart rate will be assessed. 
Treatment Credibility and Expectancy. The 18-item Treatment Credibility/Expectancy Questionnaire (CEQ; Devilly & 
Borkovec, 2000) will be used to examine whether treatment expectancy or credibility varied between PSRT+DCS and 
PSRT+PBO and the relationship between these constructs and treatment response. We will administer the scale after 
the first treatment sessions of PSRT+DCS and PSRT+PBO protocols.  
Patient Adherence. Patient adherence will be assessed by taking attendance at each session. Adherence to the nicotine 
patch usage will be assessed at Weeks 1-8 following the quit date.  
Therapist Adherence. Each session (for those participants who give consent to be videotaped) will be videotaped and 
10% will be rated shortly thereafter by independent raters to assess therapist adherence to, and competence with, the 
treatment protocol. Participants are not required to be videotaped and will indicate on their consent form whether or 
not they are willing to participate in the recording of sessions. 


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Concurrent Treatment. Use of medications other than nicotine patch or other aids to smoking cessation and 
participation in any concurrent psychotherapeutic treatment will be assessed at each assessment point.  
Safety Monitoring and Concerns. At each visit, participants will be asked about side effects of the study medication, 
nicotine patches, and treatment.  Adverse Events and Severe Adverse Events forms will be utilized to track any 
symptoms expressed during weekly check-ins. Forms will be reviewed each visit by the study PI, and participants who 
report significant symptoms or adverse reactions will be interviewed separately to determine whether the patch should 
be discontinued or the dose reduced. Participants who discontinue the patch or change the assigned dose will continue 
their treatment.  
AlcoBreath Screening. At each of the three study visits during which participants are asked to take medication (sessions 
3-5), participants will be asked to breathe into an AlcoBreath tube in order to assess for the presence of alcohol before 
they are administered the study medication.  
Facial recognition task 
At baseline and follow-up participants will complete a computerized task that takes approximately 5-8 minutes.  The 
task is currently in use in our lab (IRB: 2016_02_0139). Facial stimuli depicting the same adult Caucasian male with either 
a fearful or a calm facial expression will be selected from the standardized and validated NimStim Faces Set (Tottenham 
et al., 2009). Morphing software for Windows (Version 3.1, M. Fujimiya) was used to nonlinearly morph the images in 
10% increments from the extreme ends (0% to 100%) between two identities, or within the same identity between 
neutral and fearful facial expression. The fearfulness morphs are the same identity changing on expression of fear. The 
“target” is the facial stimulus that must be recognized, which is the fearful face (100% morph). The learning phase 
involves eight 2-second presentations of the target stimulus. Following each presentation, participants are shown 
another facial stimulus and asked to identify whether it is the same as the target. In the memory phase of the 
experiment, there are five blocks of 12 randomly presented facial stimuli (11 morphs and 1 completely different 
identity) and participants have to identify which are the same as the target from the previous phase.  The purpose of the 
first phase is for participants to learn procedures and the target image. The purpose of the second phase is to test for 
generalization of recognition to the morphs that resemble the target images on a gradient of emotional expression or 
identity. Participants’ responses and reaction times are recorded. 
  
Assessment Schedule 
Participants will receive thorough assessments prior to and over the course of this study. The schedule of assessment 
visits is such that it allows us to (1) compare smoking cessation outcomes in the present study to that observed in 
previous studies and (2) carefully examine the proposed therapeutic mechanisms of action. A tabular synopsis of the 
intervention and assessment data collected throughout the study is provided in the table below.  


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The University of Texas at Austin                                                                                                          Page 14 of 29  
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Table 2. Schedule of assessments 
Protocol Weeks 
>-3 
-2 
0 
1-2 
3 
4 
5 
6 
7 
9 
13-29 
Measures 
Pre-
Scre
en 
Scree
ning 
Assess
ment 
Baseli
ne 
 
 
 
WK 0 
Quit 
Week 
 
WK 1 
WK 2 
 
WK 4 
 
WK 8, 
10, 16, 
24 
Screening  
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
Smoking history* 
X 
X 
 
 
 
 
 
 
 
 
 
Motivation to quit 
smoking* (20 items) 
 
X 
 
 
 
 
 
 
 
 
 
SCID 
 
X 
 
 
 
 
 
 
 
 
X 
(week 
29) 
Medical    
history 
 
X 
 
 
 
 
 
 
 
 
 
Laboratory testing (blood 
draw, pregnancy test6) 
 
X 
X6 
 
X 
 
 
 
X 
X6 
X6 
C-SSRS 
 
X 
 
 
 
 
 
 
 
 
 
Post-Cessation Smoking 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
Point Prevalence 
Abstinence 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Timeline Follow-Back  
 
 
 
 
 
 
 
 
 
 
X 
Carbon Monoxide 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Saliva Cotinine 
 
 
 
 
 
 
 
 
 
X 
X 
Nicotine Dependence and 
Withdrawal 
 
 
 
 
 
 
 
 
 
 
 
FTND* 6 items 
 
X 
 
 
 
 
 
 
 
 
 
QSU* 10 items 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
MWS* 15 items 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Abstinence 
Expectancies Questionnaire 
(SAEQ) 28 items 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Smoking Cessation Self-
Efficacy (SE) 43 items  
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Smoking Cue Appeal 
Survey (SCAS) 8 items  
 
 
X 
 
 
 
 
 
 
 
X 
Barriers to Cessation Scale 
(BCS) 19 items  
 
X 
 
 
 
 
 
 
 
 
 
Smoking Consequences 
Questionnaire-Brief (SCQ-
Brief) 25 items  
 
X 
 
 
 
 
 
 
 
 
 
Intolerance for Smoking 
Abstinence Discomfort 
(IDQ-Smoking) 17 items 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Mood, Emotion, and 
Cognition 
 
 
 
 
 
 
 
 
 
 
 
Inventory of Depression 
and Anxiety Symptoms 
(IDAS) 64 items  
 
 
         X 
 
X 
 
X 
 
X 
X 
X 


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Difficulties with Emotion 
Regulation Scale (DERS) 36 
items  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
NEO-FFI 60 items  
 
X 
 
 
 
 
 
 
 
 
 
Regulatory Focus 
Questionnaire (RFQ) 11 
items 
 
X 
 
 
 
 
 
 
 
 
 
Sleep, Financial Strain, 
Life Stressors 
 
 
 
 
 
 
 
 
 
 
 
Financial Strain 
Questionnaire (FINSTR) 8 
items  
 
X 
 
 
 
 
 
 
 
 
 
Impulsivity 
 
 
 
 
 
 
 
 
 
 
 


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Delay Discount 
Questionnaire 27 items  
 
 
X 
 
 
 
 
 
 
 
X 
UPPS 59 items  
 
 
X 
 
 
 
 
 
 
 
X 
Panic Severity 
 
 
 
 
 
 
 
 
 
 
 
Panic Attack Questionnaire 
(PAQ)  
X 
 
 
 
 
 
 
 
 
 
 
PDSS* 7 items  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anxiety Sensitivity, 
Distress Intolerance and 
Negative Affect 
 
 
 
 
 
 
 
 
 
 
 
ASI-III* 18 items  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DII 10 items  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANAS* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief Pain Inventory 
 
 
X 
 
 
 
 
 
 
 
X 
Treatment 
Integrity/Acceptance 
 
 
 
 
 
 
 
 
 
 
 
Credibility/Expectancy 
 
 
 
X4 
 
 
 
 
 
 
 
Therapist Adherence1 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Patient Adherence2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent Treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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The University of Texas at Austin                                                                                                          Page 18 of 29  
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AlcoBreath Screening5 
 
 
 
 
X 
X 
X 
 
 
 
 
Vital Signs 
 
 
X 
 
 
 
 
 
 
 
 
Face Task  
 
 
 
 
 
 
 
 
 
 
 
Facial Recognition Task  
 
 
X 
 
 
 
 
 
 
X 
X 
Note. Shaded areas refer to measures of mediator variables. *These measures are completed as online questionnaires. 
1,2 Patient adherence and therapist competence will be monitored separately and the schedule will vary. 3Adverse events 
will be assessed for DCS/PBO and NRT. 4Administered at the end of session 1. 5Alcohol screening will be completed prior 
to each of the three sessions which include DCS/PBO administration. 6The pregnancy test is the only one that will be 
completed at intake and monthly following randomization(SV2, 7, 13, 21, and 29). The remaining lab testing will only 
occur should the physician see fit.  
6. PARTICIPANTS  
A. TARGET POPULATION 
Our target enrollment is 80 participants who complete all study procedures. However, we will recruit 4,000 
participants between the ages of 18 and 65 to account for dropouts and ineligible participants. We have chosen 
to study adult daily smokers who have had a panic attack within the past year and use nicotine to regulate their 
emotions. Although subjects will be excluded at intake for use of certain psychotropic medications, we believe it 
would be unethical to prevent them from starting these medications once the study has begun. Thus, we will 
assess for the initiation of psychotropic medications throughout treatment and utilize this information when 
analyzing the study results. Participants evidencing suicidal ideation at screening will be referred to treatment 
and excluded from the study. 
Inclusion of Women and Minorities 
Those who do not have adequate command of the English language will not be included in the study. All 
materials for the study including the measures are written in English and developing psychometrics for non-
English speaking populations is beyond the scope of this project. If eligible, participants will be enrolled without 
regard to ethnic background. To increase minority participation, we will utilize a multimedia campaign with the 
following strategies: flyers in information booths at community and church functions, and placement of flyers in 
retail outlets and organizations known to serve minorities. We will use the aforementioned recruitment 
strategies in a sustained manner in the hope of boosting minority enrollment to 40%; we have achieved this 
level of minority recruitment in recent studies using these methods (Hofmann, Meuret, Smits et al., 2006; 
Zvolensky, Feldner et al., 2005). 
Inclusion of Children 
 
 
 
 
 
 
 
 
 
Participants below the age of 18 (and adults above 65 years old) will not be included in the proposed research 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 19 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
study for several reasons. First, the study hypotheses are not directly relevant to children or older adults without 
significant modification to take into account differing cognitive and developmental issues as well as issues 
related to smoking metabolism. These different issues could manifest in behavior, affect, psychophysiology, 
and/or neurobiology. If children and older adults were to be included, the study design would, at a minimum, 
have to take these factors into account and hypotheses would have to be added. To do so, the sample size 
would have to be increased considerably to yield adequate power to test these additional hypotheses. The 
budget allocation for an individual project simply does not allow for this possibility without seriously 
compromising other aspects of the study. Second, we elected not to include individuals below the age of 18 for 
two significant reasons. One reason is that individuals below the age of 18 experience markedly lower rates of 
smoking and anxiety-related problems than do adults (Fiore et al., 2000, 2008; Ollendick, Mattis, & King, 1994). 
Given these findings, it is most parsimonious to sample adults at this stage of treatment development. A second 
reason is that it has been repeatedly hypothesized that panic problems are rare among children due to their 
limited cognitive capacities (Nelles & Barlow, 1988; Vasey & Daleiden, 1994). Specifically, youths have a limited 
ability to attribute anxiety to internal cues or associating the sensations of anxiety with mental or physical 
catastrophe, a process central to the AS construct. Thus, restricting this initial investigation of AS and smoking to 
adult participants will help eliminate concerns regarding the cognitive capacities of children.  Additionally, if 
children were to be included, the study design would, at a minimum, have to take these factors into account and 
additional hypotheses would need to be added. To do so, the sample size would have to be increased 
considerably to provide for adequate power to test these new hypotheses. Therefore, to focus on individuals 
below the age of 18 years does not make practical or clinical sense or offer help in developing more 
generalizable data. 
B. INCLUSION/EXCLUSION  
 
Inclusion Criteria:  
• 
Male and female patients ages 18-65 capable of providing informed consent  
• 
Willing and able to provide informed consent, attend all study visits and comply with the protocol 
• 
Daily smoker for at least one year 
• 
Currently smoke an average of at least 8 cigarettes per day 
• 
Report a motivation to quit smoking in the next month of at least 5 on a 10-point scale 
• 
Evidence of panic attack within the past year and endorsement of smoking as an emotion regulation strategy 
(i.e., score at least a 78 on the SAEQ). 
 
Exclusion Criteria:  
• 
Subjects who do not use smoking as an emotion regulation strategy   
• 
Current diagnosis of a psychotic, eating, developmental or bipolar disorder 
• 
Significant suicide risk as determined by structured interview 
• 
Pregnant women, lactating women, and women of childbearing potential who are not using medically accepted 


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The University of Texas at Austin                                                                                                          Page 20 of 29  
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forms of contraception (e.g., IUD, oral contraceptives, barrier devices, condoms and foam, or implanted 
progesterone rods stabilized for at least 3 months).   
• 
Psychoactive substance abuse or dependence (excluding nicotine dependence) within the past 6 months 
• 
Current use of isoniazid or ethionamide compounds 
• 
A history of significant medical condition and/or be deemed as currently unhealthy by the study physician 
• 
Limited mental competency and the inability to give informed, voluntary, written consent to participate 
• 
Current use of any pharmacotherapy or psychotherapy for smoking cessation not provided by the researchers 
during the quit attempt 
• 
Concurrent psychotherapy initiated within three months of baseline, or ongoing psychotherapy of any duration 
directed specifically toward treatment of anxiety or mood disorder other than general supportive therapy 
initiated at least 3 months prior to the study 
• 
Use of other tobacco products 
• 
Plans to move outside of the immediate area in the next six months 
• 
Insufficient command of the English language 
 
C. BENEFITS 
 
Participants will have opportunity for direct benefit in the care and treatment of cigarette smoking. The 
population of adult smokers in general has a great opportunity for benefit since the results of the study may be 
valuable in the treatment of smoking. If we find that DCS augments PSRT, then smokers could elect this 
augmentation strategy to improve their quality of life. Further, the proposed study (i.e., design, assessment 
schedule, and analyses) offers the potential to improve the understanding of the mechanisms that underlie 
these effects. Thus, the anticipated benefits of the study are twofold: the results will be used to advance 
understanding of the factors related to anxiety and relapse to smoking after attempts at smoking cessation, and 
significant knowledge about the combined effects of cognitive-behavioral treatment for anxiety related 
vulnerabilities and the nicotine patch will be obtained. Participants can potentially benefit from the smoking 
cessation and panic reduction treatment provided as part of the study. The results of the study will have 
implications for matching treatments to specific characteristics of smokers. 
D. RISKS 
 
The risks associated with participating in this study are minimal. Potential risks also include nicotine patch side 
effects. Common side effects include local skin irritation at the site of the patch, and mild nausea if the 
participant continues to smoke at a high level while using the patch, and temporary vivid dreams. Less common 
are allergic skin reactions.  
The possible side effects for d-cycloserine include: headache, confusion, tremor, vertigo, memory difficulties, 
paresthesias (itching or tingling of the skin), seizure, drowsiness, confusion, dizziness, drowsiness, irritability, 
restlessness, depression, muscle twitching, trembling, nervousness, and speech problems. However, these side 
effects are most commonly related with doses greater than 500mg/day (i.e., chronic dosing), which is two times 
the amount that participants will receive in this study. DCS is a safe medication in the dosage provided; indeed 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 21 of 29  
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10-fold doses are safely administered in chronic doses in other applications. Participants will be asked not to use 
any alcohol prior to the sessions and prior to the assessments. They will also be asked to breathe into a tube so 
that members of the study team can perform a test for the presence of alcohol. It should be noted that patients 
have been given acute 250mg doses in a previous study of obsessive compulsive disorder and 1000mg doses in a 
previous study of depression, with no significant adverse side effects associated with the administration in 
either study (Heresco-Levy et al., 2013; Storch et al., 2007). This dose of 250mg was selected for the current 
study as accumulating evidence suggests that a dose of 250mg may be more likely than a lower dose to aid the 
type of therapeutic learning that is the focus of the smoking cessation intervention that we will employ in this 
protocol.  
 
 
Other potential risks include temporary nicotine withdrawal symptoms after quitting. Discomfort related to 
smoking cessation may include such symptoms as increased anxiety, irritability, difficulty concentrating, 
headaches, nausea, decreased heart rate, fatigue, increased hunger, and tobacco cravings. These symptoms are 
typical of nicotine withdrawal and result from the addictive nature of nicotine. Although symptoms of nicotine 
withdrawal may be uncomfortable, they are not harmful. It should be noted that participants in this study have 
already had numerous experiences with these sensations and feelings throughout their day-to-day life. 
There are no absolute contraindications to the use of d-cycloserine in combination with other antibiotics. There 
are potential interactions with isoniazid and ethionamide compounds; current use of isoniazid or ethionamide 
compounds is listed as an exclusion criterion (see page 17). 
The nicotine withdrawal state is primarily mediated by central and peripheral nicotinic acetylcholine activity. In 
rodent models, d-cycloserine has been shown to decrease nicotine self-administration therefore suggesting it 
may have an ameliorative effect on craving and withdrawal states. As an NMDA partial agonist, it is unlikely it 
will exacerbate nicotine withdrawal and there is no animal or human evidence it would exacerbate nicotine 
withdrawal. 
There are no known risks associated with saliva cotinine and carbon monoxide analyses. The procedures for 
obtaining these samples are brief, safe, and minimally uncomfortable. Some participants may experience minor, 
short-term discomfort with these procedures.  For example, some individuals may find it slightly uncomfortable 
to hold their breath for 15 seconds, as required for the carbon monoxide analysis. In addition, some individuals 
may report brief dry mouth following the saliva cotinine procedure.  
The exposure-based treatment offered may make some patients anxious during the exposure procedures, but 
these procedures are generally very well accepted and are associated with treatment benefit (Gould et al., 
1997). The assessment instruments may cause mild distress because of their focus on emotional topics 
associated with mental health. 
 
Protection of Human Subjects from Research Risk  


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The University of Texas at Austin                                                                                                          Page 22 of 29  
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Adequacy of Protection Against Risks 
The therapists are advanced doctoral students who are trained to identify a panic attack, and to help the patient 
recover. Specifically, the therapist will remind the patient that he/she is experiencing a false alarm, instruct the 
patient to breathe through the nose in order to reduce hyperventilation, and encourage the patient to allow the 
panic attack to run its course. Immediately following a panic attack, the therapist and patient will discuss the 
panic attack experience. This discussion is aimed to help the patient correct false beliefs regarding the 
consequences of panic attacks. The PI, Jasper Smits, Ph.D., is available for intervention as needed and back-up 
plans are established including involvement of the study physicians and referral to a hospital emergency 
department. These safety procedures have been effective in dealing with adverse physical and mental health 
events in previous and ongoing studies. Upon study completion, all participants will be referred to follow-up 
care if needed.  
If the person is in imminent danger of harming him/herself, the interview will be stopped and 911 will be 
called. If the person is not in imminent danger, but seems to be in need of psychological services for suicidality, 
they will be encouraged to call the counseling center if he/she is a student or a local community agency if he/she 
is a community participant, to set up an appointment. The interviewer will make one follow-up call to the 
participant in the week following the assessment to ascertain whether he/she made the appointment and to get 
the name of the counselor he/she has been assigned to in order to inform the counselor of the participant’s 
suicidality.  If the participant decides not to make an appointment, no further action will be taken by Dr. 
Smits.  If the participant makes the appointment and gives the name of the counselor, Dr. Smits will call the 
counselor within 24 hours to inform the counselor of the participant’s suicidality (accompanied by the release of 
information form).  If the participant is currently in therapy, Dr. Smits will call his/her therapist within 24 hours 
of the assessment if possible (accompanied by a release of information form) in order to inform the therapist of 
the participant’s suicidality. 
To minimize skin reactions due to nicotine patch, smokers will be instructed to move the site of patch placement 
each day and not repeat site use for at least one week. Smokers who smoke 4 cigs/day for 4 days will be asked 
to discontinue the patch until they are able to cut down or quit smoking again. The initial mg/day dose may be 
adjusted downward to 14 mg or 7 mg if there is significant nausea or other adverse reactions. Smokers will be 
instructed to remove the patch before bed if it significantly interferes with sleep. The patch will be discontinued 
entirely if severe skin reactions develop. Additionally, at each visit, participants will be administered a side effect 
and symptom profile. The most common side effects from using the nicotine patch are local skin irritation, 
nausea if the dose is too high (or if the patient continues to smoke at a high level while using the nicotine patch), 
and disturbed sleep and vivid dreams. Instructing the participant to rotate the site where the patch is applied 
and to remove the patch at night if sleep disturbance is impairing function will minimize these side effects. 
Participants will indicate on a checklist their incidence and severity of side effects. Checklists will be reviewed 
each visit by study personnel, and participants who report significant symptoms or adverse reactions will be 
interviewed separately to determine whether the patch should be discontinued or the dose reduced. Likewise, 
study staff will be available at all times to answer questions and concerns regarding symptoms. Participants who 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 23 of 29  
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discontinue the patch or change the assigned dose will be kept in the remaining treatment. We will track such 
changes to determine whether they affect outcomes. As noted in our previous trials, we have had little to no 
emergence of side effects with the patch (Zvolensky et al., 2008). Nonetheless, we will specifically query for 
potential side effects at each visit. 
In regard to withdrawal symptoms, there is a strong likelihood that most study participants will experience some 
nicotine withdrawal symptoms, including anxiety, restlessness, anger, irritability, sadness, problems 
concentrating, appetite change and weight gain, insomnia, and decreased heart rate. Because all participants 
will use the nicotine patch, this should diminish the overall severity of withdrawal discomfort, although the 
patch will not necessarily eliminate withdrawal discomfort entirely. Moreover, withdrawal symptoms are usually 
short-lived, with most symptoms abating within 1-2 weeks. During treatment, research team staff will monitor 
patients for development of severe psychological problems (e.g., depression) during each of our sessions and 
follow-up visits. Using the study instruments and clinical interviews, therapists will determine whether 
treatment or additional treatment for a specific psychological problem is needed and work with the patient to 
refer them to appropriate service centers. 
Regarding the administration of DCS, the prescribing psychiatrist will be Carlos Tirado, M.D., M.P.H., F.A.S.A.M. 
Dr. Tirado will review the medical history of patients (for exclusion factors), and will prescribe the three doses of 
study medication (DCS vs. PBO) to be taken during assessment weeks (weeks 3-5). Patients will be encouraged 
to call the study physician should they experience any side effects or have any questions regarding the 
medication.  
To deal with the potential risk of loss of privacy (judged to be minimal), we will maintain confidentiality by 
numerically coding all data, by disguising identifying information, and by keeping all data in locked file drawers. 
Video recordings will be coded by participant ID and will be deleted after therapist adherence ratings. 
Participant information will be accessible only to research staff. Identifying information will not be reported. 
Functions of the Data and Safety Monitoring Board (DSMB) 
A Data and Safety Monitoring Board (DSMB) will be created as an independent body charged with ensuring that 
the safety of study subjects is protected and that the scientific goals of the study are being met. To support 
those purposes, the DSMB will review any proposed amendments to the study protocol, perform expedited 
monitoring of all serious adverse events, perform ongoing monitoring of drop-outs and non-serious adverse 
events, determine whether study procedures should be changed or the study should be halted for reasons 
related to the safety of study subjects, and perform periodic review of the completeness and validity of data to 
be used for analysis of safety and efficacy. The DSMB will also ensure subject privacy and research data 
confidentiality. Members of the DSMB include the PI (Jasper Smits, Ph.D.), the Co-PIs (Michael Otto, Ph.D., and 
Michael Zvolensky, Ph.D.); Conall O’Cleirigh, Ph.D. (Chair), Mark Pollack, M.D.; Carl Lejuez, Ph.D.; and Norman 
Schmidt, Ph.D. 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 24 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
As in any clinical trial, it is not possible to anticipate all possible adverse events. We do extensive training with 
our staff on ascertaining, monitoring, and documenting adverse events. The study investigators have extensive 
experience in clinical trials organization and management, including data safety monitoring for single site and 
multi-site trials. We have established procedures for rendering first aid and life threatening emergencies. Dr. 
Smits will oversee these procedures. 
Reporting Mechanisms of AEs/SAEs to the IRB and NIDA 
Unblinded Reporting. Safety information for this study will be reported to the DSMB in an unblinded manner. A 
statistical penalty will not be assessed for the ongoing unblinded review of safety by the DSMB. Unblinded data 
will not be released to the investigators unless necessary for safety reasons. 
Range of Safety Reporting to the DSMB. It is considered necessary for the purpose of monitoring the safety of 
the study that the DSMB review not only adverse events (AEs) and serious adverse events (SAEs), but other data 
that may reflect differences in safety between treatment groups. This includes treatment retention rates, and 
reasons for drop-out. 
Serious Adverse Events. Expedited review will occur for all events meeting the FDA definition of Serious Adverse 
Events (SAEs) – i.e., any fatal event, immediately life-threatening event, permanently or substantially disabling 
event, event requiring or prolonging inpatient hospitalization, or any congenital anomaly. This also includes any 
event that a study investigator or the DSMB judges to impose a significant hazard, contraindication, side effect, 
or precaution. For purposes of this study, all SAEs will be required to be reported to the DSMB, regardless of any 
judgment of their relatedness to the study treatment. All relevant information will be reported to the DSMB for 
each SAE including information about the event and its outcome, concomitant medications, the subject’s 
medical history and current conditions, and all relevant laboratory data. Notification by e-mail, and FAX 
transmittal of all related study forms shall be made to the DSMB within 2 days of the occurrence of any SAE. 
Information will be reviewed and a determination made of whether there was any possible relevance to the 
study. Additional reporting to the IRBs will be done within 24 hours of the SAE; reporting to NIDA will be made 
according to the regulations governing SAE reporting. 
Non-Serious Adverse Events. At periodic intervals, the DSMB will be provided with unblinded summaries of the 
numbers and rates of adverse events by treatment group. These reports will include types of events, severity, 
and treatment phase. Data on individual non-serious adverse events is not expected to be needed for this 
review. 
Other Safety-Related Reports. Throughout the course of the study, the DSMB will receive unblinded summary 
reports of treatment retention and reasons for drop-out.  
Collection and Reporting of AEs and SAEs 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 25 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
Information regarding AEs is to be obtained by questioning or examining the subject. At each visit all new 
complaints and symptoms (i.e., those not existing prior to signing of informed consent) must be recorded on the 
AE Form. Pre-existing complaints or symptoms that increased in intensity or frequency after having signed the 
Informed Consent Form must be entered on the AE Form also. All AEs must be characterized in terms of their 
start and stop dates, start and stop times, intensity, action taken on Intervention, relationship to Intervention, 
subject outcome and whether or not the AE led to a Serious Adverse Event (SAE). Any clinically relevant increase 
or decrease to the intensity or frequency of a reported AE requires a separate entry on the AE Form. If the event 
meets the definition of an SAE, the procedure for reporting SAEs must be followed; the event should not be 
reported on the AE Form also incase the start and stop dates are equal to the start and stop dates of the SAE. 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that: 
• 
Results in death; 
• 
Is life-threatening;  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; or 
• 
Is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered serious too. 
All serious events occurring between signing of the Informed Consent Form by the subject and signing of the End 
of Trial Form by the investigator, except those pre-specified in the protocol, must be reported as soon as 
practical (within 24 hours of awareness) to the IRB and the DSMB. This includes serious events, which could be 
associated with the trial procedures, even if occurring outside the treatment period. 
Follow-up of SAEs, which occurred during the trial, should in principle take place until resolution of the SAE. 
Under this protocol, the following event(s) will not be considered as (an) SAE(s) and should not be entered on 
the SAE form: 
• 
Pre-planned hospitalizations for diagnostic, therapeutic, or surgical procedures for a pre-existing 
condition that did not worsen during the course of a clinical trial. These pre-planned hospitalizations 
must be entered on the medical history form, including the condition requiring hospitalization. 
• 
Hospitalizations for uncomplicated delivery. 
 
All SAEs (i.e. including serious events occurring outside the treatment period) must be reported as soon as 
practical (within 24 hours of awareness) to the IRB and DSMB. Reporting of an SAE must be done by means of 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 26 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
the SAE form. For each SAE, the investigator fills out this SAE form (as complete as possible) and sends the form 
and all available supporting documentation by fax. 
 
 
Suicidality Plan 
Endorsement of suicidal ideation will be assessed for level of risk. Low risk ideation (i.e. have thoughts or wishes 
to be dead with no plan or intent to hurt themselves) will be assessed at every session for changes to the risk 
level. Those with high risk ideation (i.e. has a plan and date in mind) will be sent a referral list that includes a 
24/7 national hotline that they can call if necessary. Research personnel will communicate with the PI right away 
for supervision and will assess for appropriate procedures as necessary. Procedures include referral to 
counsellors, plans to get them to the hospital, and/or calling the police.     
 
E. RECRUITMENT 
Subjects will be recruited from the community and from physician referrals. Any subjects meeting the entrance 
inclusion criteria will be provided the opportunity to participate in this study. Recruitment sources include: 1) 
posting newspaper and Craigslist advertisements; 2) utilizing fliers, pamphlets, and handouts in community-
based organizations, bulletin boards, stores, and handing them out at events and various other sites; 3) utilizing 
social media sites (e.g., Facebook, Twitter, LinkedIn) to post status updates with links to our online prescreen; 4) 
utilizing ResearchMatch; and 5) seeking organizations (eg. Live Tobacco Free Austin). It is noteworthy that these 
recruitment strategies have been, and are currently being, used to recruit smokers from the community for 
previous studies run in the Anxiety and Health Research Laboratory at the University of Houston (PI: Dr. 
Zvolensky) and have been used effectively at the Anxiety Research and Treatment Program at Southern 
Methodist University (PI: Dr. Smits). 
F. OBTAINING INFORMED CONSENT 
Any subjects meeting the entrance inclusion criteria will be provided the opportunity to participate in this study. 
The consent form will be sent to participants via REDCap before the baseline appointment so that they have 
time to read through the form and give their informed consent. If a participant has not yet signed the consent 
form before the baseline session, we will give them the consent form to read over and sign. Research associates 
obtaining consent will explain the study procedures and answer any questions the potential participant might 
have. Informed consent will be obtained from all participants prior to undergoing any screening procedures. 
Participants may be asked to give signed consent on an electronic device such as an iPad using REDCap. 
Participants will read the consent form on the device, print their name, and sign using their finger or stylus 
directly onto the iPad. We will either provide them with a paper copy, or email them a copy of the consent form 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 27 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
for their records, depending on their preference. All paper consent forms will be kept in locked cabinets with ID 
numbers to assure each participant has signed a consent form for at least 3 years. All electronic consent forms 
will be housed in REDCap, which will be password protected and only accessible by the PI and study personnel. 
The Institutional Review Board at the University of Texas (UT) consists of independent bodies of reviewers. 
Research associates and physicians will receive training regarding procedures required to obtain informed 
consent, and training is completed yearly in order to continually reinforce such procedures.  
The Prescreen Survey informed consent will detail procedures about the prescreen survey and screening 
assessment. Participants will read and give informed consent by clicking “I Agree” before continuing on with the 
survey. A waiver of documentation is requested for the prescreen survey informed consent procedures. All 
eligible participants will give signed, informed consent for the rest of the study procedures once they come into 
the lab for their first visit.  
7. PRIVACY AND CONFIDENTIALITY 
 
Data and Safety Monitoring Plan 
Data Entry Methods 
Our general policy for data management is that research assistants copy all data files and these files are brought to Dr. 
Smits on a weekly basis. Data forms and accompanying narrative summaries will undergo a systematic and rigorous 
editing process before they are keyed into the database. The research assistants routinely evaluate the data and discuss 
any problems and questions with the study staff and Dr. Smits at regular weekly team meetings. Accuracy of data entry 
will be ensured by a standard double-entry procedure. Data management formal reports on record status across the 
three following domains will be employed: entered, verified, and edited. These reports of data records will be evaluated 
one time a month during the final team meeting of the month. To help ensure data protection, backup copies, 
automatically generated by our computer systems, will be available. Additionally, our hard copy record systems, as 
described previously, will be maintained in fire-resistant locked cabinets. 
This study will utilize a web page-internet data collection and management system used in previous work. All data for 
the current study including demographic information, diagnoses, laboratory values, medication counts, and participant 
and clinician rated measures will be directly entered into an electronic case report form (eCRF). The eCRF will be entered 
into a dedicated computer at the University of Texas maintained by Dr. Smits in his capacity as chief study data manager.  
The eCRF will consist of a series of separate web pages for study personnel and participants. A series of passwords will 
be programmed to ensure that participants are unable to access pages reserved for study personnel. The eCRF will be 
constructed so that all requested information must be entered into each page in the fields provided, or the system will 
not permit access to the next page. The system is designed so that only completed eCRFs can be transmitted. If 
information for a field is either not available or not applicable, the system will require that it be documented as such in 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 28 of 29  
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the eCRF. Field parameters will be specified such that suspect values are either disallowed or flagged for the immediate 
attention of the study directors and Principal Investigators.  
At each visit a hard copy of the eCRF will be printed and promptly reviewed, signed, and dated by the investigator for 
clinician rated measures and by the participant for participant rated measures. A print out of the data will then be made, 
authenticated (with signature and date) by the investigator and participant and kept in the participant’s study file.  
Some study data (eCRF) will be collected and managed using Qualtrics and REDCap. Qualtrics and REDCap are high-end 
web survey tools that have been used in experimental research and is designed in a way that ensures the security of 
data transmission and protection. Qualtrics and REDCap offers Transport Layer Security (TLS) encryption (HTTPS) and 
survey security options like password protection and HTTP referrer checking. Qualtrics and REDCap are HIPAA 
compliant, and servers are stored in a tier one data storage facility that includes adequate security measures. 
 
CONFIDENTIALITY OF THE DATA OR SAMPLES 
 a.  Describe how data or samples (i.e., blood, salvia, tissue, etc.) will be collected. 
• 
Saliva samples will be collected using salivettes (Sarstedt, Rommelsdorf, Germany), which are plastic 
vials with cotton dental rolls inside. 
b. Describe how the data or samples will be securely stored and how you will achieve this. 
• 
Once the samples are collected, they will be frozen and stored (-80 degrees C) for future processing. To 
extract saliva, the samples will be centrifuged at 4 degrees C for 5 minutes at 2000 xg. They will be 
assayed with an enzyme immunoassay at Salimetrics, LLC, located in State College, PA, using a 
commercial kit (Diagnostic Products Corporation, Los Angeles, CA).  
c. Provide the length of time the data or samples will be kept.  
• 
Salimetrics, LLC will immediately dispose of the cotinine samples once the information needed is 
collected. 
d. Describe whether data or samples will be kept confidential (i.e., data can potentially be linked to participants) 
or anonymous (i.e., impossible to link data and participants).  You must include if the data or samples will be 
shared by other researchers for research purposes not detailed in this study. 
• 
The results of cotinine analyses will be kept confidential and will not be returned to participants in this 
study. Further, tubes will be identified by participant identification numbers only. Staff processing the 
cotinine samples will not have access to any identifying information of the participants. 
e. If the data or samples will be destroyed, describe when and how the destruction will occur. 
• 
Salimetrics, LLC will take all precautions and dispose of the cotinine samples in a biohazard disposal. 
8. COMPENSATION 
 
Participants will be paid $25 for the baseline visit, $10 for weeks 1, 2, 4, 5, 6, and 7, $15 for week 3, and $20 


Research Proposal 
 
 
 
The University of Texas at Austin                                                                                                          Page 29 of 29  
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine- 09/8/2014 
 
 
each follow-up (Weeks 9, 13, 15, 21, 29). Thus, participants can receive up to $200 for their participation in the study. 
These payments are not contingent upon smoking status at the time of assessment or follow-up. We feel this amount is 
appropriate in order to assure that all participants involved with the study have the means to attend assessment visits, 
thus aiding our goal of evaluating treatment efficacy at various time points.  
 
 

SAP_001.pdf: 
 
                      
 
 
 
 
 
 
 
Enhancing Panic and Smoking Reduction Treatment with D-Cycloserine 
NCT01944423 
 
Last updated: 6/7/2017 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Data Analysis.    
Overview. First, we will assess the equivalence of the treatment groups on key baseline 
variables (demographics, smoking characteristics, psychological variables); variables on which 
the groups differ will be used as a covariate in final analyses. We will then examine missing data 
patterns, dropout rates (see below), and distributional properties of measures and use 
transformations to improve distributions when necessary.   
Following recommendations of the Society for Research on Nicotine and Tobacco (Hall et al., 
2001), the effects of treatment on PPA will be examined using Generalized Linear Mixed Models 
(GLMM), employing the logistic linking function. In our GLMM analyses, the repeated measures 
will be nested within individuals, which will be nested within their treatment cohort, thereby 
appropriately accounting for correlated scores within the small cohorts. Our GLMM analysis will 
model outcome as a curvilinear (quadratic) or exponential function of time (based on AIC and 
BIC) since PPA is expected to decrease rapidly at first and then level off over time. Using this 
model, one can test differences between treatment groups by including treatment condition as 
an “individual level” predictor of 
rate 
of 
decrease 
in 
PPA 
over 
time. 
We 
can also examine treatment group differences in PPA at any assessment point. Multi-
level models (MLMs) similar to the GLMM models will be used to test treatment differences 
in continuous outcomes (the psychological variables: withdrawal symptoms, negative affect, 
panic severity, distress intolerance, and anxiety sensitivity). All models will include relevant 
control variables (e.g., gender, education, nicotine dependence, etc.). We will also run a Cox 
proportional hazards survival analysis predicting risk of lapsing or relapsing to smoking and 
compare the two conditions on these outcomes.   
Tests of specific aims. Aim 1a: Treatment differences in slopes will indicate different rates 
of decrease in PPA. To determine whether there are treatment differences in PPA at any particular 
time point (e.g., week 24), we will center the “Time” variable in the GLMM model at that time point 
(Singer & Willett, 2003). Aim 1b: Cox proportional hazard models will be used to test for 
differences between treatments in relative risk of lapse and relapse, and in time to first lapse and 
to relapse. Aim 2a: The same analyses in Aim 1a will be used in MLMs to test for treatment 
differences in the psychological outcomes (withdrawal symptoms, negative affect, panic 
severity, distress intolerance, anxiety sensitivity). Aim 3a: The “a” paths in our mediation model 
(see Figure 1 in Specific Aims) will be calculated as in Aim 2a. Because we expect the “a” paths 
to be moderated, separate analyses will be conducted to calculate the “a” paths for each treatment 
condition (Tein, Sandler, MacKinnon, & Wolchik, 2004). The “c” path will be calculated as in Aim 
1a. Aim 3b: The “b” paths in our mediation model will be the regression coefficients for the 
mediators when all the mediators are simultaneously added to the GLMM equation predicting 
PPA used in Aim 1a. Aim 3c. Tests of the mediated pathways will be conducted separately for 
each treatment condition (due to moderated mediation [Tein et al., 2004]). Significance of 
mediated pathways will be determined using Bayesian bootstrap mediation analysis (Yuan & 
MacKinnon, 2009).  
 Missing Data. Following Hall et al. (2001) and Enders (2011), we will use pattern mixture 
modeling to assess the effect of missing data. We will rerun our analyses coding for various 
missing data patterns (no missing data, sporadic missing, dropouts, etc.) to determine both if 
missingness 
impacts 
our 
findings 
and 
how 
the 
differences 
between PSRT+DCS and PSRT+PBO depend on the missing data pattern.  


Power Analysis. Because we will have a sample size of 80, this application is not powered 
to detect small differences between treatment conditions. However, consistent with the aims of a 
Stage IB study, our primary goal is determining 1) the feasibility of the new intervention and 2) 
whether a Stage II study is warranted. Below we estimate (for the lowest powered analyses) the 
effect sizes (ESs) that we will be able to detect as statistically significant with 80% power.   
Aim 
1a: 
GLMM 
model 
comparing 
PPA 
in 
the PSRT+DCS condition 
vs. 
the PSRT+PBO condition. We 
performed 
a 
Monte 
Carlo 
study 
to 
calculate 
the 
minimum PSRT+DCS PPA rate detectable by our analysis. Our assumptions were: an average 
of 5 assessments per participant (71% of the post quit date assessments) (Zvolensky et al., 
2008) and a 27% PPA in PSRT+PBO at the last follow-up (Piper et al., 2010). We examined 
numerous PSRT+DCS PPA rates to determine the lowest rate detectable by our analysis, 
performing 1000 simulations for each PPA rate. The results indicated that we would have 
.80 power to detect a significant treatment effect if the PPA rate in PSRT+DCS at the follow-up 
was 43% or greater. This difference – i.e., 43% vs. 27% - is equivalent to a Cohen’s ώ effect size 
(the effect size measure for proportions) of .17, between a small (.10) and medium (.30) ώ effect 
size (Cohen, 1988). Thus, we have sufficient power to detect a smaller than medium effect.  
Aim 3: Moderated Mediation of changes in PPA. The first step in our moderated mediation 
power analysis was to determine the power to detect moderation of the “a” path (see Figure 
1. Using the MLM power analysis program PinT 2.12 (Snijders & Bosker, 1993) to calculate our 
power to detect moderation of path “a”, we found that we had over .95 power to detect a medium 
effect size (d = .50) for moderation of the “a” path. Next we calculated the power to detect 
longitudinal mediation for each treatment group, over time. For this analysis, path “a” was the 
slope of change in the mediator over time, and path “b” was the relation between the mediator 
and the outcome over time. We performed a Monte Carlo study to calculate the power for a 
bootstrap mediation analysis. We assumed that the effect sizes for the “a” paths (the change in 
the mediators over time) would be large (d>.80; see 3C.2a), the effect size for the “b” paths would 
be medium, and the PPA rates were assumed to be those found in Aim 1a (27% for PSRT+PBO 
and 43% for PSRT+DCS). The Monte Carlo study consisted of 400 samples, for each of which 
we 
performed 
a 
bootstrap 
mediation analysis 
each consisting 
of 
1000 
resamples. Results indicated that we would have at least .81 power to detect a mediated effect.