Clinical trial NCT01842334
Conditions: Nicotine Dependence Smoking Cessation
Keywords: Nicotine Dependence Smoking Cessation D-cycloserine
Sponsor: Mclean Hospital
Start date: 2013-04-01; Completion date: 2017-08-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
1. Compare the relative efficacy of ten weeks of once weekly 250 mg D-cycloserine (DCS) vs. placebo (both in conjunction with cognitive behavioral therapy (CBT) and nicotine replacement therapy (NRT) on reducing cigarette smoking in treatment-seeking nicotine-dependent outpatients.
2. Compare the relative efficacy of ten weeks of once weekly 250 mg DCS vs. placebo on the process of extinction and the memory encoding process.

Detailed description:
The investigators will conduct a Stage 1 pilot feasibility study at McLean Hospital to develop a medication to treat nicotine dependence. In a randomized, double-blind, placebo-controlled trial, 40 nicotine-dependent participants ages 18-65 will receive cognitive behavioral therapy (CBT) and nicotine replacement therapy (NRT) over a 10- week period, with half receiving D-cycloserine (DCS) pretreatment and half receiving placebo. Participants will receive either 250 mg DCS or placebo prior to weekly CBT sessions in addition to NRT over a 10-week treatment period. The investigators also aim to determine the effects of DCS on performance on neuropsychological tests. A 10-week treatment period will be followed by follow-up assessments including neuropsychological tests at 1 and 3 months post-treatment. Primary outcomes will include smoking as measured by carbon monoxide levels and self-report measurements.

Arms: arm 1: 250 mg D-cycloserine once weekly an hour before receiving cognitive behavioral therapy treatment along with Nicotine Replacement Therapy. arm 2: one placebo capsule once weekly an hour before receiving cognitive behavioral therapy treatment along with Nicotine Replacement Therapy
Interventions: intervention 1: Cognitive Behavioral Therapy intervention 2: Nicotine Replacement Therapy
Intervention descriptions: intervention 1: CBT administered to to both DCS and placebo group. intervention 2: NRT administered to both DCS and placebo group.

Protocol documents:
Prot_SAP_000.pdf: 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Kevin P. Hill, M.D., M.H.S. 
 
PROTOCOL TITLE 
D-cycloserine (DCS) Pretreatment + Cognitive Behavioral Therapy and Nicotine 
Replacement  Therapy for Smoking  Cessation 
 
 
FUNDING 
American Lung Association Clinical Patient Care Research Grant. 
 
 
VERSION DATE 
9/10/15 
 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
A.  Compare the relative efficacy of ten weeks of once weekly 250 mg DCS vs. placebo 
(both  in  conjunction  with  CBT and  NRT)  on  reducing  cigarette  smoking  in 
treatment-seeking nicotine-dependent outpatients. 
 
B.  Compare the relative efficacy of ten weeks of once weekly 250 mg DCS vs. placebo 
on the process of extinction and the memory encoding processes. 
 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Smoking remains an enormous public health problem.  Despite advances in 
available medications and behavioral interventions, it remains difficult to quit. At the 
completion of this exploratory, proof-of-concept study, we hope to have improved our 
understanding of the relationship of DCS to smoking cessation as well as have gained a 
better understanding of the relationship of DCS, extinction, and the memory encoding 
process. The addition of DCS to a CBT and NRT program may improve the efficacy of 
CBT and NRT for smoking cessation and may also provide additional evidence 
supporting a similar combination treatment for other substance use disorders.  This 
study may be translatable to other disorders because it targets a learning process as 
opposed to a specific receptor.  If tests of neuropsychological performance provide 
information about how DCS may affect smoking cessation treatment, further work could 
help to predict characteristics that would make certain smokers more likely to respond 
to a particular treatment.  This would help move the field of substance abuse treatment 
toward greater treatment individuation. Thus, with this proposal, we hope to take steps 


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toward developing an integrative treatment for nicotine dependence, an important public 
health problem that affects millions of Americans. 
 
 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
a. Overview 
We will conduct a Stage 1 pilot feasibility study at McLean Hospital to develop a 
medication to treat nicotine dependence. (FIGURE 1) In a randomized, double-blind, 
placebo-controlled trial, 40 nicotine-dependent participants ages 18-65 will receive 
cognitive behavioral therapy (CBT) and nicotine replacement therapy (NRT) over a 10- 
week period, with half receiving D-cycloserine (DCS) pretreatment and half receiving 
placebo.  Participants will receive either 250 mg DCS or placebo prior to weekly CBT 
sessions in addition to NRT over a 10-week treatment period. We also aim to determine 
the effects of DCS on performance on neuropsychological tests.  A 10-week treatment 
period will be followed by follow-up assessments including neuropsychological tests at 1 
and 3 months post-treatment.  Primary outcomes will include smoking as measured by 
carbon monoxide levels and self-report measurements. 
 
b. Source of subjects and recruitment methods 
Forty participants ages 18-65 with DSM-IV diagnosis of nicotine dependence will be 
recruited from McLean Hospital outpatient programs and from the Boston area via 
newspaper advertisements, flyers, Craigslist online ads, clinician referrals, and word-of-
mouth. 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
a. Recruitment and Intake 
 
Interested individuals will respond to advertisements by leaving a message (first name 
and call back number only) in the BPRL recruiting voice mailbox.  Research assistants 
will call them back with 24 to 48 hours and conduct an initial phone screen that takes 
about 15 minutes.  It will cover basic inclusion and exclusion criteria, as well as a brief 
description of the study to determine if the person is interested in participating. If the 
volunteer is appropriate and agrees to participate, they will be invited to come to the 
BPRL for a physical and psychiatric evaluation (SCID).  Treatment alternatives will also 
be offered to the prospective participant if they decide not to participate or are not 
eligible for participation. 
The 75-minute initial assessment interview will be done by a research assistant and 


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study physician.  Once participants have given informed consent, they will undergo a 
comprehensive evaluation that includes medical, psychiatric, and drug use histories as 
well as physical, psychiatric, and laboratory examinations and the following screening 
procedures:  a)  Detailed  history  of  cigarette  use;  b)  Review  of  DSM-IV  criteria  for 
nicotine dependence; c) Medical history and concomitant medication record; d) Physical 
examination; e) Laboratory screen that includes CBC, electrolytes, and BUN/creatinine; 
f) Expired CO level; g) Urinalysis; h) Urine pregnancy test for women; and i) 12 -lead 
electrocardiograph (ECG). The study physician will make the final decision to enroll.   
  
b. Informed consent 
Eligible participants will complete standard consent documentation.  Prior to the 
participant being asked any question about his/her health, the participant will be given a 
consent form to read.  The research assistant will go over it in detail with the participant 
and answer any questions the participant may have concerning the study.  A study 
physician will then also review the study procedures and ask the subject to provide 
his/her informed consent.  If enrolled in the study, consent to communicate with their 
other clinicians will be obtained as well.  Clinicians will be notified of their patients’ 
enrollment in the study, thus allowing them to carefully monitor for changes in mood 
while in they are undergoing treatment to stop use of nicotine.  Treatment alternatives 
will be offered to the prospective participants if they decide not to participate or are not 
eligible for participation. 
 
c. Randomization 
Study participants will be randomized to receive either DCS or placebo and 
stratified according to baseline expired CO level (10-20 ppm and >20 ppm). 
 
a.1. Availability and Flow of Subjects into Treatment 
After approximately 240 telephone screens, we plan to conduct in-person 
screens of 40 individuals in the course of 18 months to achieve our desired 
sample size.  Based our prior smoking-related studies, we estimate that there will 
be approximately 16 potentially eligible participants per month from treatment 
programs at McLean Hospital and the other Boston area recruitment methods 
and an adequate flow of participants to meet our target of 2.5 participants per 
month. 
 
a.2.   Study  Visits and Participant  Payments.    Each  weekly visit  over  10 
weeks  will include a 50-minute CBT session and dispensing of pills. Research 
assessments will take place at 4 and 10 weeks of treatment and 4 and 12 weeks 
post-treatment.   See Table D.1, Schedule of Measures.  Participants will earn 
$50 for the initial screen, $20 for each of the 10 Actiwatch/Diary visits, a $10 gift 
card for the completion of additional neuropsychological assessments at week 3, 
$50 for each of the 4 Follow-Up Interviews, and a bonus $50 for diary 
completion, for a total of $510.   Medication and therapy will be provided at no 
cost. 
 
a.3.  Clinical Emergencies.  If a participant is intoxicated, the participant will be 
evaluated medically, sent home in a taxi when safe, and the appointment re-
scheduled.   If a participant experiences a problem that requires clinical 


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intervention during the course of the study (e.g., mania, suicidal ideation, or 
dangerous intoxication), we will evaluate the situation medically, make an 
appropriate recommendation, and help the participant to implement this plan.    
This could involve hospitalization at McLean, referral to the hospital's outpatient 
program, or other medical or psychiatric treatment, as clinically appropriate. 
 
b. Drugs to be used 
b.1.  D-cycloserine. D-cycloserine (DCS)(Seromycin®, The Chao Center, West 
Lafayette, IN) is an FDA-approved broad spectrum antibiotic for the treatment of 
tuberculosis. 
Participants will be randomized to receive either placebo or DCS 250 mg, given 1 hour 
prior  to weekly CBT sessions.   The McLean Research Pharmacy will randomize the 
participants and dispense medication or placebo weekly to the study physician, who 
  
 
will deliver a prescription to the pharmacy days in advance of the CBT session. The 
medication will be purchased from McKesson by the PI.  The dose is based upon prior 
clinical trials of patients with psychiatric disorders (Norberg et al. 2008).  Norberg et al. 
(2008) showed that timing of the dose significantly predicted effect size; their meta- 
analysis found that the greatest enhancement of animal extinction or human exposure 
therapy  was  seen  when  DCS  was  given  immediately  prior  to  or  after 
extinction/exposure. 
Participants will be assessed for side effects prior to each medication administration.  
If side effects preclude a participant from continuing study medication, the medication 
will be discontinued, but the participant will continue to be followed for follow-up 
assessment visits.  While our group recognizes the importance of medication adherence 
in substance use disorder patients, the once-weekly dosing of DCS mitigates many 
adherence issues. 
 
b.2.  Nicotine Replacement Therapy.  Transdermal nicotine patches delivering 21-, 14-, 
and 7-mg/24 hours will be purchased from CVS by the PI.  Nicotine patches will be 
distributed to volunteers at the initial assessment session and at the 6- and 8-week 
follow-up sessions.  Participants smoking 15 of more cigarettes per day will start with a 
21-mg patch and those smoking 10-15 cigarettes per day or who cannot tolerate a 21- 
mg patch will start with a 14-mg patch.  Participants starting with a 21-mg nicotine patch 
will use it daily for 6 weeks, followed by a taper to a 14-mg nicotine patch daily for 2 
weeks and, finally, a 7-mg nicotine patch daily for 2 weeks.  The others will start with a 
14-mg patch used daily for 8 weeks followed by a 7-mg patch used daily for 2 weeks. 
We will discuss possible side effects of nicotine with volunteers and ask them to report 
these symptoms or any others they experience.  Adverse event forms will document any 
side effects experienced while using the patch. 
 
c. Devices to be used 
N/A. 
 
d. Research Measures: Data to be collected 
d.1. Diagnostic Assessment of Smoking. To make the diagnosis of nicotine 
dependence, the Structured Clinical Interview for DSM-IV (SCID) (First et al. 1996) will 
be used. 


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d.2.   Self-Report  of  Smoking.    Participants  will  receive  a  packet  of  1  page,  self- 
addressed, prepaid postage Daily Diary pages. The diary consists of questions about 
smoking and other drug use as well as eating and sleeping habits.   We have had 
excellent compliance with these diaries in the past.  During the weekly visits, we plan to 
collect cigarette use data using the Timeline Follow Back (TLFB) (Sobell and Sobell, 
1992) protocol. 
 
d.3.  Alveolar carbon monoxide (CO).  End-expiratory CO will be measured after a 10- 
second breath-hold using a P.K. Morgan CO analyzer (Chatham, Kent, UK) at baseline, 
each CBT session, and each follow-up visit.  Abstinence from cigarettes will be verified 
by an expired air CO concentration ≤10 ppm. 
 
d.4.  Other Assessments.   We developed the self-administered Drug and Alcohol Use 
Questionnaire (Weiss et al. 1988), a baseline measure that addresses the context of 
lifetime and recent drug and alcohol use, as well as sociodemographic data.  Function 
in multiple spheres of the participants’ lives will be obtained at baseline and monthly 
using the LIFE functional assessment (Keller et al. 1987).   HIV risk behaviors will be 
assessed at baseline and weeks 10, 14, and 22 with the Risk Assessment Battery 
(Metzger 1992).  To assess treatment services outside the study that patients use, we 
will administer the Treatment Services Review (TSR) (McLellan et al. 1992) at baseline 
and monthly. The Client Satisfaction Questionnaire (CSQ-8) is an 8-item self-report 
scale will assess satisfaction with treatment. The Quick Inventory of Depressive 
Symptomatology   (QIDS-SR)   is   a   short   self-report   questionnaire   for   depressive 
symptoms used successfully in the STAR*D project. At baseline and week 3, several 
standard self-report questionnaires will be used to assess cigarette craving: Tiffany 
QUS Brief  form,  nicotine  withdrawal:  Wisconsin  Smoking  Withdrawal  Scale,  and  
affect: Positive and negative affect scales (PANAS). Menstrual cycle phase information 
also will be collected in women. 
 
d.5. Neuropsychological Assessment. (see Appendix for description of assessments) 
We  will  use  a  brief  battery  of  standard,  well-known  neuropsychological  tests 
designed primarily to evaluate general intellectual capacity and executive/attentional 
functions. All test scoring will be completed blind to participants' clinical ratings. The 
WASI 4-subtest version (Vocabulary, Similarities, Block Design and Matrix Reasoning) 
is a reliable, brief assessment used to obtain IQ estimates (Weschler 1981).  The Rey 
Auditory  Verbal  Learning  Test  (RAVLT)  assesses  immediate  memory  span,  new 
learning, susceptibility to interference, and recognition memory (Lezak et al. 2004).  The 
Stroop Color Word Task challenges the ability to inhibit inappropriate responses and 
resist interference (Bush et al. 2003).  The Multi-Source Interference Task (MSIT) has 
been shown to reliably and robustly activate cingulo-frontal-parietal circuitry associated 
with cognitive/attentional pathways (Bush and Shin, 2006).   The Go/No Go Task is a 
task of inhibitory control (Menon et al. 2001). 
 
 
 
 
 


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Table D.1  Schedule of Measures 
 
Baseline only 
Physical examination                                                     
Structured Clinical Interview for 
DSM-IV 
Menstrual Cycle Info. ( Women only) 
Drug and Alcohol Use Questionnaire                             
Wechsler Abbreviated Scale of Intelligence                                                                     
Tiffany QUS Brief form 
Wisconsin Smoking Withdrawal Scale                           
Positive and Negative Affect Scales (PANAS)  
Baseline and week 3 
Tiffany QUS Brief form                                                   
Wisconsin Smoking  Withdrawal Scale                                                                               
Positive and Negative Affect Scales (PANAS) 
Menstrual Cycle Info. (Women Only) 
 
Baseline, weeks 10, 14, and 22 
ECG                                                                               Laboratory testsa 
Rey Auditory Verbal Learning Test                               Stroop Color Word Test 
Multi-Source Interference Task 
                                Timeline Followback Functional 
Assessment (from the LIFE) 
                                Risk Assessment Battery        
Quick Inventory of Depressive Symptomatology 
Fagerstrom Test for Nicotine 
Client Satisfaction Questionnaire-8 
                      Dependence 
 
aTests include urinalysis, electrolytes, complete blood count, & blood chemistries 
 
 
Baseline and weekly 
Daily Diary                                                                     Adverse Events & Side Effects 
Alveolar Carbon Monoxide (CO) 
 
Baseline and monthly 
LIFE                                                                               Urine pregnancy test 
Treatment Services Review 
 
8.2. Data Analysis. 
a.   For the  main outcome  measures  acquired during  treatment  and  post-treatment 
follow-up,  the  analytical  approach  will  address  the  nature  of  the  outcome  (e.g., 
categorical vs. quantitative outcomes), as well as accommodate the within-individual 
correlation  due  to  repeated  assessments.  In  addition,  the  results  from  the  given 
approach will be assessed for sensitivity to drop outs or missing data.  The primary data 
analysis will be an intent-to-treat analysis, which includes all randomized 
participants. Of note, every attempt will be made to continue assessing 
participants even if they drop out of treatment. In addition, we will replicate 
all analyses with the completers only.  The primary and secondary outcome 
variables are intended to explore various aspects of response to therapy and 


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to help define a clinically meaningful response. The primary outcome measures, 7-day 
point prevalence of abstinence, and expired CO, have been chosen for their ability to 
indicate daily use of cigarettes by relying on self-report of use. 
Specifically, for assessing the effect of DCS on smoking patterns, we propose to use 
the generalized estimating equations (GEE) approach to longitudinal analysis, 
appropriately accounting for the positive correlation among the post-baseline repeated 
binary measures of 7-day abstinence within the same individual. The GEE approach 
incorporates all of the repeated assessments on an individual and provides a more 
powerful statistical analysis than does a cross-sectional analysis that focuses only on a 
single  summary  index.    Specifically,  we  will  fit  logistic  regression  models  for  the 
repeated post-randomization binary measures of 7-day abstinence of the following 
form:logit(p) = β0 + β1*trt, where trt (treatment)=1 if randomized to DCS and trt=0 
otherwise, and p denotes the probability of 7-day abstinence. 
 
The logistic regression model will be fit using the GEE approach  (as  
implemented  in  PROC  GENMOD  in  SAS)  to  account  for  correlation among 
repeated assessments of the same individual.  The logistic regression analyses will also 
adjust for the stratification factor used in the randomization of patients.   The GEE 
analysis accounts for this within-subject correlation, and the resulting estimated β1, 
when exponentiated, provides an estimate of the treatment effect expressed as an odds 
ratio, comparing the DCS group to the placebo group. The effect of DCS on 7 -day 
abstinence will be assessed by testing Ho: β1=0. 
A relatively similar analytic approach will  be  used  to  assess  the  effect  of  DCS  on 
changes  in  expired  CO  assessments.  A linear mixed effects model will be used to 
assess changes in CO during treatment and at post-treatment follow-up. The linear 
mixed effects model will include the effects of treatment group, time and the baseline 
measure of CO; the inclusion of random effects accounts for the correlation among the 
12 post-baseline CO measurements (1-per week during 10 weeks of treatment, plus 
week 14 and 22). We will  adjust  for  the  dose  of NRT  by  including dose  as  an 
additional   covariate    in    the    linear    mixed    effects   model   analysis    of   the 
treatment  comparison (DCS vs.  placebo).  The linear mixed effects model includes 
random intercepts and random slopes for time to appropriately account for correlation 
among repeated measures of CO and heterogeneity of variance over time; the model 
will be fit using PROC MIXED in SAS. 
  
Analyses of secondary  outcomes  will  focus  on  assessing  the  effect  of  DCS 
on neuropsychological assessments. For example, linear mixed effects models will also 
be used to analyze quantitative/continuous neuropsychological outcomes (e.g., MSIT 
response accuracy and times), with appropriate transformation (e.g., log transformation) 
of the outcome as necessary. To examine the effect of DCS on changes in 
neuropsychological  performance during treatment, the linear mixed effects model will 
include the effects of treatment condition and the baseline measure of the 
neuropsychological outcome.  Additional analyses of secondary outcomes will focus on 
the number of days of cigarette smoking during treatment and post-treatment follow-up. 
Frequency of days of cigarette use will be analyzed via a log-linear (or Poisson) 
regression model, controlling for pre-treatment frequency of days of cigarette use. 
Although log-linear regression methods are considered appropriate for the analysis of 
count or frequency data, in many biomedical applications, count data have variability 
that far exceeds that predicted by the Poisson distribution; we expect that days of 
cigarette use will not be an exception. This phenomenon, known as overdispersion, will 
be  accounted  for  in  the  planned  regression  analysis  through  the  inclusion  of  a 


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dispersion parameter.     The log-linear regression analyses will be fit using PROC 
GENMOD in SAS. 
 
b.  Missing Data and Dropout.  With repeated assessments, missing data are 
inevitable. Incomplete data pose 2 concerns for inference:   bias and efficiency.   We will 
use statistical methods (GEE and linear mixed effects models) that incorporate partially 
observed data on participants who drop out.  We will provide detailed descriptions of the 
patterns of missing data and assess the sensitivity of results to different assumptions 
about the mechanism by which data are missing.  For example, pattern-mixture models 
can be used to assess the sensitivity of results to informative dropout or missing data. 
Dr. Garrett Fitzmaurice, our biostatistician consultant, is an expert in handling missing 
data in longitudinal studies (Fitzmaurice et al. 2004). 
 
c.  Sample Size and Power.  We plan to randomize 20 participants per group for a total 
of 40 subjects.  This sample size will provide a reasonable estimate regarding the effect 
size for a subsequent larger trial. With a total of 40 participants, and assuming a Type-I 
error level (alpha-level) of 0.05 (two-sided), a 7-day abstinence prevalence of 25% in 
the placebo group, the study would have approximately 80% power to detect medium 
effect sizes, corresponding to risk ratios of 2.3-2.6 (as the within-participant correlations 
ranges from 0.3-0.7). For example, with moderate within-participant correlation (ρ=0.5), 
the study would have 80% power to detect a risk ratio of 2.48. 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
The standard of care for nicotine dependence is psychotherapy and/or medication; our 
treatment attempts to strengthen the best available treatment by enhancing the 
behavioral intervention. 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
Care will be taken to minimize risk. In addition to carefully screening prior to enrollment, 
we have weekly visits during which we will carefully monitor response to medication or 
placebo with respect to side effects and changes in mood. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
Safety Monitoring. 
D-cycloserine has been shown to have a favorable safety profile in studies; it has been 
well-tolerated in several clinical trials and no adverse events have been reported (Santa 
Ana et al. 2009; Storch et al. 2010; Evans and Drobes, 2008; Goff et al. 2008). 
Nonetheless, we will monitor safety through standardized methods.    Presence and 
severity of side effects will be obtained through a standard Adverse Events Checklist as 
well  as the  “Frequency  and  Intensity  of  Side  Effects  Rating/Global  Report  of  Side 


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Effects Burden” (Weiss, 2004), a 2-minute questionnaire that assesses the frequency, 
intensity, and level of burden of side effects.  We will have a low threshold for obtaining 
additional medical workup during the study if the participant reports medical symptoms. 
Based  on  the  literature  on  the  effects  of  DCS,  we  anticipate  few  adverse  events 
(Norberg et al. 2008).  However, if a participant has a clinically significant laboratory or 
other medical abnormality that cannot be attributed to another cause, the participant’s 
medication will be discontinued and the participant will be followed for follow-up 
assessment visits only. If a participant is intoxicated, he/she will be evaluated medically, 
sent home in a taxi when safe, and the appointment rescheduled.   If a participant 
experiences a problem that requires clinical intervention during the course of the study 
(e.g., mania, suicidal ideation, or dangerous intoxication), we will evaluate the situation 
medically, make an appropriate recommendation, and help the participant to implement 
this plan.     This could involve hospitalization at McLean, referral to the hospital's 
outpatient program, or other medical or psychiatric treatment, as clinically appropriate. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
a. Drug side effects and toxicities 
 
D-cycloserine has been shown to have a favorable safety profile in studies; it has 
been well-tolerated in several clinical trials and no adverse events have been reported 
in these studies (Santa Ana et al. 2009; Storch et al. 2010; Evans and Drobes, 2008; 
Goff et  al.  2008).    Most  adverse  reactions  occurring  during  therapy  with  D-
cycloserine involve the nervous system or are manifestations of drug hypersensitivity 
(Seromycin package insert).  Nervous system side effects appear to be related to higher 
doses (500 mg daily or above) and include drowsiness, headache, tremor, psychoses, 
and hyperirritability.  Sudden development of congestive heart failure has been reported 
in patients receiving 1 to 1.5 g of D-cycloserine daily.  Nicotine can cause headache and 
skin irritation. 
 
b. Psychosocial risks 
 
There is a low likelihood that participants previously screened for significant 
psychiatric disorders will be triggered by content of therapy sessions.  As mood may be 
affected, we will monitor mood and suicidal ideation weekly with the Columbia Suicide 
Severity Scale. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
a.   Potential benefits to participating individuals 


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Participants may be able to stop or reduce their smoking, which would have enormous 
health and financial benefit to them. 
 
b.   Potential benefit to society 
Smoking remains an enormous public health problem.  Despite advances in available 
medications and behavioral interventions, it remains difficult to quit.  At the completion 
of   this   exploratory,   proof-of-concept   study,   we   hope   to   have   improved   our 
understanding of the relationship of DCS to smoking cessation as well as have gained a 
better understanding of the relationship of DCS, extinction, and the memory encoding 
process.  The addition of DCS to a CBT and NRT program may improve the efficacy of 
CBT and NRT for smoking cessation and may also provide additional evidence 
supporting a similar combination treatment for other substance use disorders.   This 
study may be translatable to other disorders because it targets a learning process as 
opposed to a specific receptor.   If tests of neuropsychological performance provide 
information about how DCS may affect smoking cessation treatment, further work could 
help to predict characteristics that would make certain smokers more likely to respond 
to a particular treatment.  This would help move the field of substance abuse treatment 
toward greater treatment individuation.  Thus, with this proposal, we hope to take steps 
toward developing an integrative treatment for nicotine dependence, an important public 
health problem that affects millions of Americans. 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
Men, women, and minorities will all be recruited.  Pregnant women and children will be 
excluded in part due to the lack of data on the safety of D-cycloserine in these groups. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
Proficiency in English is necessary for a long-term treatment study that includes 10 CBT 
sessions and ensures that the participants can properly convey any subtle side effects 
that relate to their safe participation in this study. 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
 
 
 
RECRUITMENT PROCEDURES 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
11 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
a. Inclusion Criteria. 1) Age range 18-65 years; 2) DSM-IV diagnosis of nicotine 
dependence, based on the Structured Clinical Interview for DSM-IV (SCID) (First et al. 
1996); 3) express a desire to quit cigarette smoking within the next 30 days; 4) smokes 
greater  than  or  equal  to  10  cigarettes per  day  and  less  than  or  equal  to  20 
cigarettes per day; 5) an expired carbon monoxide (CO) determination greater than or 
equal to 10 ppm over ambient values; 6) for women of childbearing age, a negative 
pregnancy test at screening with agreement to use adequate contraception to prevent 
pregnancy and multiple subsequent pregnancy tests; 7) consent for us to communicate 
with their prescribing clinician; 8) furnish the names of 2 locators, who would assist 
study staff in locating them during the study period; 9) live close enough to McLean 
Hospital to attend study visits; 10) plan to remain in the Boston area for the next 4 
months; and 11) are willing and able to sign informed consent. 
 
Exclusion Criteria. 1) Current diagnosis of other drug or alcohol dependence (other than 
nicotine and opioid dependent participants on agonist or antagonist pharmacotherapy); 
2) significant cardiac disease; 3) current serious psychiatric illness or history of  
psychosis,  schizophrenia,  bipolar  type  I  disorder  (taking  psychiatric  medications, 
aside  from  wellbutrin,  is  not  an  exclusionary  criterion);  4)  have  a  current  medical 
condition (including significant laboratory abnormalities, such as liver function tests >5 
times the upper limit of normal range) that could prevent regular study attendance; 5) 
have mental retardation or organic mental disorder; 6) exhibit acutel y dangerous or 
suicidal behavior; 7) are pregnant, nursing, or, if a woman of childbearing potential, not 
using a form of birth control judged by the Principal Investigator to be effective;  8) 
current  NRT or other smoking cessation treatment; 9) current CBT for smoking 
cessation; 10) current smokeless tobacco use; 11) inability to read or write in English; 
12) has epilepsy. 
 
 
b. Source of subjects and recruitment methods 
 
 
Forty participants ages 18-65 with DSM-IV diagnosis of nicotine dependence will 
be recruited from McLean Hospital outpatient programs and from the Boston area via 
newspaper advertisements, flyers, Craigslist online ads, clinician referrals, and word-of- 
mouth. 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
Subject Payments.  Participants will earn $50 for the initial screen, $20 for each of the 
10 Actiwatch/Diary visits, a $10 gift card for the completion of the additional 
neuropsychological assessments at week 3, $50 for each of the 4 Follow-Up Interviews, 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
12 
and a bonus $50 for diary completion, for a total of $510. Medication and therapy will be 
provided at no cost. 
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
Eligible participants will complete standard consent documentation.  Prior to the 
participant being asked any question about his/her health, the participant will be given a 
consent form to read. The research assistant will go over it in detail with the participant. 
After answering any questions the participant may have concerning the study, he/she 
will be asked to provide their informed consent.  If enrolled in the study, consent to 
communicate with their other clinicians will be obtained as well. Clinicians will be 
notified of their patients’ enrollment in the study, thus allowing them to carefully monitor 
for changes in mood while in they are undergoing treatment to stop use of nicotine.  
Treatment alternatives will be offered to the prospective participants if they decide not to 
participate or are not eligible for participation. 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
 
 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
13 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
Safety Monitoring. 
D-cycloserine has been shown to have a favorable safety profile in studies; it has been 
well-tolerated in several clinical trials and no adverse events have been reported in 
these studies (Santa Ana et al. 2009; Storch et al. 2010; Evans and Drobes, 2008; Goff 
et   al.   2008).   Nonetheless,   we   will   monitor   safety   through   standardized 
methods. Nicotine can cause headache and skin irritation. Presence and severity of 
side effects will be obtained through a standard Adverse Events Checklist as well as the 
“Frequency and  Intensity  of  Side  Effects  Rating/Global  Report  of  Side  Effects 
Burden”  (Weiss,2004),   a   2-minute   questionnaire   that   assesses   the   frequency, 
intensity,  and  level  of burden  of  side  effects.    We  will  have  a  low  threshold  for 
obtaining additional medical workup during the study if the participant reports medical 
symptoms.   Based on the literature on the effects of DCS, we anticipate few adverse 
events (Norberg et al, 2008). However, if a participant has a clinically significant 
laboratory or other medical abnormality that cannot be attributed to another cause, the 
participant’s medication will be discontinued and the participant will  be followed for 
follow-up  assessment  visits  only.  If  a  participant  is  intoxicated,  he/she  will  be 
evaluated   medically,   sent   home   in   a   taxi  when   safe,   and   the   appointment 
rescheduled.   If a participant experiences a problem that requires clinical intervention 
during the course of the study (e.g., mania, suicidal ideation, or dangerous intoxication), 
we will evaluate the situation medically, make an appropriate  recommendation,  and 
help  the  participant  to  implement  this  plan.     This could involve hospitalization at 
McLean, referral to the hospital's outpatient program, or other medical or psychiatric 
treatment, as clinically appropriate. 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
14 
The Principal Investigator assumes responsibility for ensuring informed consent, 
data management, and the detection and reporting of adverse events.  In general, the 
data to be reviewed will include screening data, baseline data, efficacy data, safety 
data, quality assurance data, accrual status including projections, and any other data 
that will help in the assessment of the effectiveness of the clinical trial.  
The risk associated with participating in this study is moderate. D-cycloserine has 
been established as a safe treatment for tuberculosis. Consequently, serious side 
effects associated with this treatment are not expected. There will be on-call medical 
coverage to respond to any adverse events throughout the clinical trial.  
The Principal Investigator will conduct a review of all adverse events and 
determine the attribution and grade of severity of the adverse event by using the 
following scales: 
 
 
Attribution of Risk Categories: 
Definite:  Adverse event(s) will clearly be related to investigational agent(s) or other 
intervention 
Probable: Adverse event(s) will likely be related to investigational agent(s) 
Possible: Adverse event(s) may be related to investigational agent(s) 
Unlikely:  Adverse event(s) will doubtfully be related to investigational agent(s) 
Unrelated: Adverse event(s) will clearly not be related to the investigational 
agents(s) 
 
Grades of Risk: 
0:  No adverse event or within normal limits 
1:  Mild adverse event 
2:  Moderate adverse event 
3:  Severe adverse event resulting in hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect 
4:  Life-threatening or disabling adverse event 
5:  Fatal adverse event 
 
Serious adverse events (SAEs) include any untoward medical occurrence that at any 
dose results in death or the immediate risk of death, hospitalization or the prolonging of 
an existing hospitalization, persistent or significant disability/incapacity or a congenital 
anomaly/birth defect. Participants will be terminated from participation if the investigator 
feels that participants' health or well-being may be threatened by continuation in the 
study. Serious unanticipated adverse events will be reported within 48 hours to the 
Partners IRB. The principal investigator will evaluate the adverse event and determine 
whether the adverse event affects the Risk/Benefit ratio of the study and whether 
modifications to the protocol are required. In addition, he will conduct a review of all 
adverse events at least semi-annually, and he will evaluate the frequency and severity 
of the adverse events and determine if modifications to the protocol or consent form are 
required. 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
15 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
The research assistants will be responsible for day-to-day monitoring of the 
validity and integrity of the data.  Dr. Hill will meet with the research assistants to 
discuss data monitoring on a monthly basis and will sample participant data folders 
monthly as well. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf  
          
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_Events.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
All data collected will be de-identified with participant ID numbers and used for research 
purposes only.  Written records will be kept in a locked file cabinet in a locked office.   
They will be destroyed after 7 years.   Computerized data files will also be de- identified 
with subject ID numbers and kept in a password protected file on a password protected 
computer. 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
16 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
Not applicable. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.