E-cigarettes to Promote Smoking Reduction Among Individuals With Schizophrenia
Phase: NA
Conditions: Tobacco Smoking
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
E-cigarettes to Promote Smoking Reduction Among Individuals With Schizophrenia 
 
NCT02918630 
 
Version Date: 05/17/2017 
 
 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
ABSTRACT 
This pilot feasibility project will assess reducing tobacco cigarette smoking among individuals with serious 
mental  illness  (SMI)  by  providing  access  to  an  electronic  nicotine  delivery  system  (e-cigarette).  SMI 
populations of interest will consist of individuals with schizophrenia, schizoaffective disorder, bipolar disorder, 
and post-traumatic stress disorder  (PTSD). Preliminary data will be used to inform and support a future NIH 
application to ultimately conduct a full-scale clinical trial to evaluate the efficacy of e-cigarettes as an 
intervention to treat tobacco addiction in adults with SMI. 
Rates of tobacco smoking are 2-4 times higher among individuals with SMI compared to those without 
mental illness and the rate of smoking decreases has lagged behind that of the general population 1,2. Tobacco 
smokers with SMI are more dependent on nicotine and less likely to quit compared to those without mental 
illness 3-5. Tobacco-smoking related death and morbidity are high among individuals with SMI, with half the 
deaths in this population due to tobacco related cancers, respiratory diseases, and cardiovascular conditions 
6,7. Predominate theories point to a number of potential causal mechanisms including but not limited to: 1) 
alleviation from negative symptoms and cognitive deficits associated; 2) genetic, environmental, and neural 
deficits that increase vulnerability to tobacco dependence; and 3) increased susceptibility to withdrawal 
symptoms 13,14. Although tobacco smoking cessation is an ideal goal, many individuals with SMI are not 
motivated to quit tobacco smoking in the near future. As an alternative strategy, reducing tobacco smoking 
may result in more viable health gains. For example, smoking reduction has health benefits on its own and also 
increases the likelihood that smokers may initiate and succeed in quitting smoking in the future 15,16. However, 
reducing tobacco smoking also poses a number of challenges. Simply reducing the number of daily cigarettes 
smoked may have unintended consequences including compensatory increases in smoking and worsening of 
psychiatric symptoms. Additionally, two of the first-line medications for nicotine dependence (i.e., varenicline, 
bupropion)  carry  black-box  warnings  for  increased  risk  of  psychiatric symptoms and  suicidal  ideation  in 
patients with a history of psychiatric illness. 
E-cigarettes present a potential innovative solution to the challenges of reducing tobacco smoking among 
adults with SMI. E-cigarettes provide an experience close to tobacco smoking, which may increase their 
acceptability and use. The long-term health consequences of e-cigarette use are unknown. However, no 
negative health consequences of short-term use as in the current study have been reported, and most 
researchers agree that e-cigarettes are likely healthier than tobacco smoking 17. Importantly, two small open- 
label studies observed decreased tobacco smoking among non-treatment seeking adults with schizophrenia 
and schizoaffective disorder following one month of access to e-cigarettes 18,19. Such results are promising as 
individuals with schizophrenia exhibit severe tobacco smoking, even when compared to others populations 
with SMI. 
In the current pilot proposal, adults with SMI (N=10/group) interested in reducing their tobacco smoking will 
be randomized to receive either nicotine replacement therapy (NRT; patch 21 mg) as the standard of care or 
NRT plus e-cigarettes (36 mg/ml) for one month according to a double-blind, randomized controlled trial 
design. We will use a previously evaluated e-cigarette including nicotine liquid solutions that have been 
independently tested. 
 
SPECIFIC AIMS AND HYPOTHESES 
Specific Aim 1: Assess feasibility, acceptability, and safety of providing e-cigarettes to adults with SMI 
to reduce tobacco smoking. 
Hypothesis 1.a: We predict that a high proportion of participants will consent to participate (≥ 80%) and 
complete (≥ 70%) the study. 
Hypothesis 1.b: We predict that end of study participant satisfaction ratings will indicate high acceptability of 
e-cigarettes and likelihood of future use. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
Hypothesis 1.c: We predict e-cigarettes will be safe as measured by frequency of adverse events (AEs) and 
side-effects.  In addition, we predict e-cigarettes will not be associated with increases in symptom specific 
measures. 
 
Specific Aim 2:  To compare reductions in tobacco smoking between NRT vs NRT +  e-cigarettes (36 
mg/ml). 
Hypothesis 2: Significantly greater reductions in smoking (tobacco cigarettes/day, breath CO) will be 
observed in the NRT + e-cigarette vs. the NRT condition. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB APPROVAL DATE: 05/17/2017 
 
 
NUMBER:
BACKGROUND AND RATIONALE 
SMI and Increased Risk of Tobacco Smoking. Rates of tobacco smoking are 2-4 times higher among 
individuals with SMI compared to those without mental illness and the rate of smoking decreases has lagged 
behind that of the general population 1,2. Tobacco smokers with SMI are more dependent on nicotine and less 
likely to quit compared to those without mental illness 3-5. Tobacco-smoking related death and morbidity are 
high among individuals with SMI, with half the deaths in this population due to tobacco related cancers, 
respiratory diseases, and cardiovascular conditions 6,7. Tobacco smoking prevalence among adults with 
schizophrenia and schizoaffective disorder is 80-90% and Predominate theories point to a number of potential 
causal mechanisms including but not limited to: 1) alleviation from negative symptoms and cognitive deficits 
associated; 2) genetic, environmental, and neural deficits that increase vulnerability to tobacco dependence; 
and 3) increased susceptibility to withdrawal symptoms 13,14. 
Benefits of Targeting Tobacco Smoking Reduction. Cessation of tobacco smoking is ideal, but the 
majority of tobacco smokers with schizophrenia and schizoaffective disorder report no desire to quit in the 
immediate future 28,29. Therefore, a more viable strategy may be to target reducing tobacco smoking. 
Epidemiological studies have observed benefits of reduced tobacco smoking on ischemic heart disease, lung 
cancer, and chronic obstructive pulmonary disease 30, particularly when tobacco smoking reductions occur 
among  heavy  smokers  15.  However,  results  have  been  mixed  with  some  studies  reporting  no  benefits. 
Disparate results are likely influenced by compensatory tobacco smoking (longer, deeper, more frequent puffs) 
to maintain nicotine levels. Compensatory tobacco smoking can be mitigated by providing NRT. A number of 
randomized controlled trials providing NRT to promote smoking reduction have noted significant decreases in 
tobacco  smoking  accompanied  by  decreases  in  breath  carbon  monoxide  (CO)  and  cotinine  and  other 
measures of cardiovascular risk 31-34. Additionally, greater cessation was observed among those receiving NRT 
vs placebo, suggesting that tobacco smoking reduction with NRT could lead to cessation. This finding is 
supported in a meta-analysis of 10 randomized-controlled trials comparing pharmacological, behavioral, or 
combined interventions to promote tobacco smoking reduction among individuals not ready to quit 16. Results 
showed  that  both  the  pharmacological  and  combined  interventions  increased  likelihood  of  long-term 
abstinence. 
Therefore, tobacco smoking reduction can 1) improve tobacco smoking-related health risks, particularly 
when combined with access to alternative sources of nicotine; and 2) increase the future likelihood of tobacco 
smoking cessation among those with no desire to quit. However, areas of improvement still exist. For example, 
some authors in the above studies noted evidence of some compensatory tobacco smoking, albeit at a 
reduced level with NRT. Additionally, NRT compliance was identified as a target for improvement. E-cigarettes 
present an innovative solution that may address these two areas and provide an alternative source of nicotine. 
E-Cigarettes as a Novel Source of Nicotine. Since their introduction just over a decade ago, awareness 
and use of e-cigarettes has increased dramatically. E-cigarettes consist of a battery, a heating element, and 
the ability to store a liquid typically nicotine and flavor. Compared to NRT, e-cigarettes provide an experience 
closer to tobacco smoking, which may increase their acceptability and use. For example, a secondary post-hoc 
analysis of 86 individuals identified with mental illness from the ASCEND trial showed greater ratings of 
acceptability  (83%  vs  37%),  compliance  (53%  vs.  20%),  and  significantly  greater  reductions  in  tobacco 
smoking (9.9±7.0 vs. 5.7±6.3) 35 among individuals in the e-cigarette vs. NRT condition. Two open-label trials 
have examined the effects of providing e-cigarettes to non-treatment seeking tobacco-smokers with 
schizophrenia and schizoaffective disorder 18,19. Primary outcome measures differed for both studies, but 
significant reductions in tobacco smoking were observed after one month of e-cigarette access. Additionally, 
significant reductions in breath CO were observed, suggesting that compensatory tobacco smoking was 
mitigated. No SAEs were observed and the most common AEs were nausea, throat iteration, dizziness, head 
ache,  and  dry  cough.  Importantly,  one  study  noted  no  change  in  positive  and  negative  symptoms  of 
schizophrenia and schizoaffective disorder following smoking reduction, which is in accord with the results from 
other studies using NRT among those with schizophrenia and schizoaffective disordIRerB
36,37. 
 
HSC-MS-16-0667 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
There are a number of potential concerns regarding the use of e-cigarettes as an intervention for tobacco 
smoking. First, the health consequences of long-term e-cigarette use are currently unknown. However, this is 
not an issue given the current study’s duration. Overall, evidence from chemical, toxicological, and clinical 
studies designed to evaluate the safety of e-cigarettes suggests they may result in significant reduction in harm 
compared to continued use of tobacco cigarettes 17. Second, previous studies have not controlled for variability 
in levels of nicotine delivered via e-cigarettes, an important concern affecting compensatory tobacco smoking. 
The current proposal addresses this limitation by utilizing e-cigarettes that have been previously studied and by 
testing the nicotine concentrations in an independent lab 38-41, resulting in nicotine delivery that is similar to 
traditional tobacco cigarettes. 
 
METHODS 
Research Team. Dr. Yoon will serve as the PI on the current proposal. Significant collaborators include 
Drs. Cho, Meyer, Reddy, Eissenberg, Lopez, and Weaver. They have also agreed to serve as collaborators on 
future grant proposals related to the current project. Dr. Cho is an experienced research psychiatrist and 
Director of the Integrated Clinical Neuroscience and Treatment Program (ICNTP) for serious mental illness. Dr. 
Cho will assist in referring participants from the ICNTP. Dr. Meyer is clinical psychologist and expert in the field 
of bipolar disorder. He is the director of the Psychological Intervention and Research Laboratory for Mood 
Spectrum Disorders (PIRL-M). The clinic associated with PIRL-M will be helping with recruitment of patients 
experiencing bipolar disorder. Dry Reddy is a licensed clinical psychologist with expertise in the assessment 
and treatment of posttraumatic stress disorder. She is the Director of the Clinical and Translational Research 
Program on Traumatic Stress and the Stress, Trauma, and Recovery Services (STARS) Clinic. The STARS 
Clinic will recruit patients experiencing PTSD. Drs. Eissenberg and Lopez are experts in e-cigarette research. 
Many critical aspects of the current study have been informed by their research at the Virginia Commonwealth 
University Center for the Study of Tobacco Products (VCU CSTP). They have provided recommendations on 
an effective e-cigarette model and will also provide nicotine solution that has been independently tested. 
Additionally, they have provided copies of tobacco smoking and e-cigarette related questionnaires used in their 
studies, which will aid in making cross-study comparisons and also solidify future collaborative efforts. Dr. 
Weaver is the Medical Director at the Center for Neurobehavioral Research (CNRA) and has previously 
worked on a number of e-cigarette studies. He will provide medical guidance and ensure participant safety 
over the course of the study. 
Study Design and Overview. We will utilize a double-blind, randomized controlled design to assess the 
feasibility and acceptability of using e-cigarettes to reduce tobacco smoking among individuals with SMI 
(schizophrenia and schizoaffective disorder, bipolar disorder, or PTSD). Participants will consist of tobacco 
smokers with SMI interested in reducing or quitting their tobacco smoking. Note that these two experimental 
conditions were chosen based on available funds and likelihood of obtaining preliminary data that would be 
useful in a future NIH grant application. We plan to assess other conditions in the future (e.g., placebo e- 
cigarette, etc.). Following a one-week baseline lead-in period, participants will be randomized to either the NRT 
or NRT + e-cigarette condition. Study visits will be scheduled for once a week (5 weeks total). 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Overview of study design. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
Study Procedures and Assessments 
Participant Recruitment and Selection. Participants will be recruited from the ICNTP, PIRL-M, and 
STARS clinic. Eligible participants will meet the following inclusion criteria: 1) be diagnosed with schizophrenia 
or schizoaffective disorder, bipolar disorder, or PTSD and in stable medical condition (DSM-5); 2) report 
smoking ≥10 tobacco cigarettes/day and present a breath CO ≥10 ppm; 3) report wanting to quit or reduce 
their cigarette smoking; 4) be fluent in English; 5) be between 18 and 65 years of age; and 6) have a stable 
living situation. Participants will be ineligible if they meet the following  exclusion criteria: 1) be currently 
pregnant or breastfeeding; 2) report wanting to quit smoking in the immediate future; 3) test positive for illicit 
drugs except THC; and 4) have any illness, medical condition, or use of medications, which in the opinion of 
the study physicians (Drs. Cho and Weaver) would preclude safe and/or successful completion of the study. 
Following informed consent, participants will complete an initial general evaluation protocol (HSC-MS-05- 
0322; General evaluation of Eligibility for Substance Abuse/Dependence Research) to assess their psychiatric 
status, medical evaluation, and drug use history. 
E-cigarette. The e-cigarette will consist of 1) a 3.3 V, 1000 mAh battery; and 2) a 1.5 Ohm, dual-coil 
cartomizer (SmokTech; Shenzhen, China). Study staff will load the cartomizer with 1 ml tobacco flavored 70% 
propylene glycol/30% vegetable glycerin liquid containing nicotine concentrations 36 mg/ml (AVAIL; Richmond, 
Virginia, USA). Nicotine concentration will be tested at an independent laboratory at VCU (±2 mg/ml). Virtually 
every aspect of the e-cigarette (model, voltage, resistance, liquid, and nicotine concentration) has been chosen 
based on systematically conducted studies by Dr. Eissenberg and his colleagues 38-41. With these parameters, 
e-cigarettes with 36 mg/ml nicotine liquid produce blood plasma nicotine levels similar to that of tobacco 
cigarettes after 10 puffs. Participants will be provided verbal and written instructions on how to use and 
maintain the e-cigarettes at Week 1 visit. Risking of spilling nicotine liquid is minimal as the cartomizer contains 
cotton batting for liquid absorption. However, to mitigate any potential risks, participants will be provided gloves 
to be used when changing cartomizers. Additionally, they will receive pill bottles to hold spare cartomizers, 
instructed not to try and open the cartomizer, and told to keep them away from children. 
Nicotine Replacement Therapy. Participants will receive nicotine patch (21 mg) starting study Week 1. 
Participants will be instructed to apply a new patch each morning on a clean, dry, non-hairy area of skin. 
E-Cigarette and Tobacco Smoking Related Assessments. Tobacco smoking will be assessed using a 
combination of breath CO, urinary cotinine, and self-report via time-line follow-back. Standard questionnaires 
will be used to assess a number of tobacco-smoking related measures. The Fagerstrom Test for Nicotine 
Dependence (FTND) will used to assess tobacco cigarette dependence 42. The Questionnaire of Smoking 
Urges (QSU) will be used to assess craving for tobacco cigarettes 43. The Minnesota Nicotine Withdrawal 
Questionnaire (MNWQ) will be used to assess withdrawal symptoms from tobacco cigarettes 44. The Stages of 
Change Questionnaire  will be administered to assess desire to quit from tobacco cigarette smoking 45. The 
Clinical COPD Questionnaire (CCQ) will be used to assess changes in COPD-related symptoms 46. Additional 
smoking-related assessment will include the Confidence to Quit (CQ) and Hooked on Nicotine Checklist 
(HONC). E-cigarette related questionnaires developed and provided by Dr. Eissenberg will be used to evaluate 
e-cigarette dependence, patterns of use, evaluation of using e-cigarettes, and side-effects. These 
questionnaires will include Confidence to Quit, E-Cigarette Dependence Scale, E-Cigarette Patterns of Use, E- 
Cig Evaluation, E-Cig Side Effects, and Hooked on Nicotine Checklist. 
Assessing Changes in Symptoms Relevant to SMISchizophrenia. The Brief Psychiatric Rating Scale 
(BPRS) 47   will assess symptom severity among individuals with SMI. Potential changes in key cognitive 
domains associated with will be assessed with the MATRICS Consensus Cognitive Battery (MCCB). The 
Columbia Suicide Severity Rating Scale (CSSRS) will assess suicide ideation. Changes in mood 
symptomatology including also anhedonia and mania will be assessed with the Beck Depression Inventory 
(BDI),  Snaith-Hamilton  Pleasure  Scale  (SHAPS),  and  the  Altman  Self-Rating  Mania  Scale  (ASRM) 
respectively. Changes in PTSD symptoms will be assessed using the PTSD Checklist for DSM 5. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
Safety and Health-Related Measures. Adverse events (AEs) and severe AEs, along with concomitant 
medications, will be assessed at weekly study visits. Heart Rate (HR) and blood pressure (BP) will also be 
assessed using standard hospital-grade equipment. 
 
Table 1. Outline of Study Procedures and Assessments. 
 
Study Visits 
Procedure and Assessments 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Baseline Screening 
X 
Receive E-Cigarettes (36 mg/ml) and NRT Patch (21 mg) 
X 
X 
X 
X 
Smoking Related Assessments 
Breath CO, QSU, MNWQ, , TLFB, CCQ, CQ, HONC 
Urinary Cotinine 
FTND, Stages of Change 
E-Cigarette Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs, Concomitant Meds, HR, BP 
X 
X 
X 
X 
X 
X 
BPRS, CSSRS, BDI, SHAPS, ASRM, PTSD 
X 
X 
X 
X 
X 
X 
MCCB 
X 
X 
 
DATA ANALYSIS PLAN 
Preliminary data analyses will inspect baseline, group differences as well as correlations between baseline 
variables and specified outcomes. Baseline or demographic variables demonstrating a correlation with both 
predictors and outcomes, meet criteria for being potential confounders,i,ii and will result in two sets of analyses: 
one in which the relevant variable is included as a covariate and one in which it is not.  This will determine the 
degree to which any group differences might confound conclusions regarding treatment. Statistical analyses 
will use R v. 3.3.0iii and SAS v.9.3.iv 
Analyses will primarily use generalized linear modeling.  Continuous, count, dichotomous and time-to-event 
data will utilize linear, Poisson, logistic, and proportional hazards regression respectively (Proc GENMOD and 
PROC PHREG; SAS v. 9.3, function glm(); R v. 3.3.0).  Longitudinal analyses will employ generalized linear 
mixed models (Proc MIXED, Proc GLIMMIX and Proc MCMC; SAS 9.3).   Evaluation of distributional 
assumptions will use residual plots and, where possible, formal statistical tests. Depending upon statistical 
technique, transformations, robust estimators, stratification and/or scaling coefficients will address violations of 
assumptions.  Analyses of cross-sectional data with missing values will utilize multiple imputation (Proc MI; 
SAS v.9.3)v. Multiple imputation and maximum likelihood are robust to data missing at random.  Sensitivity 
analyses will permit evaluation of the robustness of findings to missing data assumptions. 
 
Specific Aim 1: Assess feasibility, acceptability, and safety of providing e-cigarettes to adults with SMI 
to reduce tobacco smoking. 
Hypothesis 1.a: We predict that a high proportion of participants will consent to participant (80%) and 
complete the study (70%) completion rate. Descriptive statistics will evaluate consent and completion rates. 
Hypothesis 1.b: We predict that end of study participant satisfaction ratings will indicate high acceptability of 
e-cigarettes and nicotine patch and likelihood of future use. Generalized linear models will evaluate the 
relationships between participant satisfaction, acceptability of e-cigarettes and nicotine patch, and likelihood 
of future use. 
Hypothesis 1.c: We predict e-cigarettes will be safe as measured by frequency of adverse events (AEs) and 
side-effects, and not associated with increases in negative symptoms (BPRS) or decreases in cognitive 
performance (MATRICS). Generalized linear modeling will evaluate relationships between adverse 
events/side-effects, negative symptoms, and cognitive performance. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
Specific Aim 2:  To compare reductions in tobacco smoking between NRT vs NRT +  e-cigarettes (36 
mg/ml). 
Hypothesis 2: Significantly greater reductions in smoking (tobacco cigarettes/day, breath CO) will be 
observed in the NRT + e-cigarette vs. the NRT condition. Generalized linear modeling will evaluate group 
differences in smoking reduction between NRT and NRT + e-cigarettes over time as measured by breath CO 
(using a Gaussian distribution) and tobacco-cigarettes/day (using a Poisson distribution). 
 
Power/Sample Size Considerations. For the current proposal, power will focus on Aim 2. Effect size is 
derived using G*Power 3.1.9.2. Assuming alpha = 0.05 and a correlation among repeated measures of 0.5, a 
sample size of n = 20 (n = 10 NRT and 10 NRT + e-cigarette) provides 80% power to detect a Cohen’s f = 0.51 
for group differences between NRT and NRT + e-cigarette. The Frequentist findings will be augmented with a 
Bayesian approach to characterize the probability that effect sizes of varying magnitude exist. 
 
JUSTIFICATION 
Results from the current pilot study will be used as preliminary data in support of a future NIH R21 grant 
submission. The immediate goal of that R21 will be to assess a longer intervention period (3 months), which is 
the standard in clinical trials, as well as additional experimental conditions (e.g., 0 mg/ml e-cigarette condition) 
to enhance the experimental rigor of the study. Based on the current results, we will also assess the need for 
additional intervention components (e.g., contingency management, motivational interviewing, etc.). Finally, we 
will also assess other indices of reduced tobacco smoking toxicity such as 4-methylnitrosamino-1-3-pyridyl-1- 
butanol (NNAL) and lung function using spirometry. The R21 will in turn lead to a future R01 application. 
Additionally, completion of the current proposal will also be beneficial in establishing a history of cooperation 
with Drs. Cho, Eissenberg, Lopez, and Weaver that will also support the competiveness of future NIH grant 
submissions on which they serve as collaborators. 

Program Director/Principal Investigator (Last, First, Middle): 
Yoon, Jin H. 
IRB NUMBER: HSC-MS-16-0667 
IRB APPROVAL DATE: 05/17/2017 
 
 
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IRB NUMBER: HSC-MS-16-0667