Clinical trial NCT02854800
Conditions: Smoking Cessation Opioid Related Disorders
Keywords: varenicline buprenorphine
Sponsor: West Virginia University
Start date: 2016-07-08; Completion date: 2017-04-10
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study was to examine the feasibility of integrating a smoking cessation intervention for cigarette smokers enrolled in an outpatient program for opioid dependence. The secondary purpose was to compare treatment effects as a function of phase in the outpatient program: 0-90 days (weekly attendance), 90 days-1 year (biweekly attendance), and more than 1 year (monthly attendance).

Detailed description:
Tobacco smoking rates are substantially higher among individuals with substance use disorders (SUDs), relative to individuals in the general population (e.g., 97% vs. 19%, respectively). Yet most treatment programs for SUDs fail to address the use of tobacco among patients, and integration of smoking cessation treatment with SUD treatment may improve outcomes for both drugs. The question remains, however, whether to implement a smoking cessation component immediately or only after a patient is stabilized on their SUD pharmacotherapy. Existing research that directly addresses this factor is limited and findings are mixed. Therefore, the purpose of this study was to compare drug use outcomes among patients at three different stages of their SUD treatment: 0-90 days (weekly clinic attendance), 90 days-1 year (biweekly clinic attendance), and more than 1 year (monthly clinic attendance) of consistent abstinence from illicit drugs. Smokers currently in treatment for opioid dependence, at the WVU Comprehensive Opioid Addiction Treatment (COAT) program, were recruited to participate in this 12-week study. Our goal was to complete 20 patients from each of the three COAT treatment groups. During the 12-week intervention period, individuals continued to attend their regular COAT clinic appointments while following a standard varenicline (Chantix®) dosing regimen and responding to questions daily via text messaging (e.g., adherence to varenicline, use of tobacco, tobacco withdrawal side effects, etc.). The primary outcomes are those relevant to feasibility: 1) recruitment, randomization, and retention, 2) adherence to medication regimen, and 3) compliance with responding to text message-based questions. Secondary outcomes include a comparison of the three COAT treatment groups on 1) relapses for all substances, 2) the proportion of smokers abstinent at each assessment (confirmed with expired air carbon monoxide samples), 3) days until successful cigarette quit day, 4) substance withdrawal and medication side effect symptoms, 5) motivation to quit tobacco, and 6) cigarette quit attempts.

Arms: arm 1: Participants in this group attended an outpatient opioid clinic once per week. As part of the current study, they received 12-week dosing of varenicline per label recommendations: 0.5mg once daily (Days 1-3), 0.5 mg twice daily (Days 4-7), and 1 mg twice daily (Days 8-84). Pill form/blister pack arm 2: Participants in this group attended an outpatient opioid clinic once bi-weekly. As part of the current study, 12-week dosing of varenicline per label recommendations: 0.5mg once daily (Days 1-3), 0.5 mg twice daily (Days 4-7), and 1 mg twice daily (Days 8-84). Pill form/blister pack arm 3: Participants in this group attended an outpatient opioid clinic once per month. As part of the current study, 12-week dosing of varenicline per label recommendations: 0.5mg once daily (Days 1-3), 0.5 mg twice daily (Days 4-7), and 1 mg twice daily (Days 8-84). Pill form/blister pack
Interventions: intervention 1: varenicline
Intervention descriptions: intervention 1: Participants followed the schedule of dosing that is specified on the label: 0.5 mg once daily (Days 1-3), 0.5 mg twice daily (Days 4-7), and 1 mg twice daily (Days 8-84).

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page 
 
Title: Smoking Cessation & Opioid Dependence Treatment Integration 
NCT Number: NCT02854800 
 
Document Date: 7/6/2016 
 


Study Protocol 
 
 
Lay Summary (6th grade reading level): 
Many people who abuse drugs also smoke cigarettes. Little is known about when in a person's drug treatment 
would be best to help them quit smoking. In this study, opioid dependent smokers will be asked to use a 
medication for 12 weeks. Each day, participants will respond to text messages related to quitting smoking. We 
will see participants once each month (4 visits) to ask about how ready they are to quit smoking. We plan to 
assess the feasibility of using this program in an opioid treatment clinic. We also plan to compare outcomes 
based on their clinic group. 
 
 
Purpose and Objectives:  Early evidence suggests that outcomes for substance use disorders (SUDs) may 
be improved for those who also smoke cigarettes, if smoking cessation is integrated with SUD treatment 
(Mannelli et al., 2013). Debate remains, however, over when to implement the smoking cessation treatment: 
immediately (to present a consistent treatment message) or after a delay (to allow patients to stabilize on their 
SUD pharmacotherapy). Thus, researchers have called for more work to determine whether the timing of 
treatment integration affects outcomes for both smoking and SUDs. At WVU, the Comprehensive Opioid 
Addiction Treatment (COAT) program provides access to a relatively large population of opioid-dependent 
smokers in various stages of SUD treatment: Days 1 to 90 (weekly group), Days 91 to 180 (biweekly group), 
and Days 181 to >365 (monthly group). In the proposed study, all three groups will receive varenicline 
pharmacotherapy and take varenicline per label instructions for 12 consecutive weeks. They will also provide a 
blood sample at one study visit for assessment of genetic markers for drug use. The goals of this work include: 
 
Primary Aims. Demonstrate the feasibility of implementing smoking cessation treatment within an 
outpatient opioid-dependence treatment program via recruitment rates, adherence to treatment 
components, compliance with study requirements, and overall retention rates. 
 
Secondary Aims. Compare COAT groups on outcomes related to drug use, including tobacco abstinence 
rates, days until successful cigarette abstinence, relapses for all drugs, withdrawal-related effects, and 
genetic markers for drug use.  
 
Study results will shed light on the feasibility of implementing smoking cessation therapy within the COAT 
clinic, results that may generalize to other treatment programs for opioid dependence. Results will also provide 
initial evidence for whether smoking cessation timing affects abstinence outcomes for both tobacco and opioid 
use. Such data are directly relevant to communities within the state of West Virginia, which are 
disproportionately affected by the harms of these drugs. Among all states, WV ranks 50th for tobacco use 
prevalence, as well as 49th for deaths related to recreational use of opioids. Ultimately, this line of work may 
lead to recommendations for improving outcomes associated with opioid dependence treatment, as well as 
improving outcomes for a population of smokers that may otherwise not quit tobacco. 
 
Explain the Scientific Rationale: Early evidence suggests that outcomes for substance use disorders (SUDs) 
may be improved for those who also smoke cigarettes, if smoking cessation is integrated with SUD treatment 
(Mannelli et al., 2013). For instance, among opioid-dependent smokers maintained on methadone (opioid 
pharmacotherapy) for up to 3 months, varenicline (tobacco pharmacotherapy) may promote an earlier 
successful cigarette quit day (de Dios et al., 2014) and improve long-term smoking abstinence rates (Nahvi et 
al., 2014), relative to placebo. Additionally, duration of smoking abstinence is associated positively with 
duration of opioid abstinence (Shoptaw et al., 2002), and changes in opioid pharmacotherapy dose are 
associated with changes in smoking behavior (Mello et al., 1985; Schmitz et al., 1994). Debate remains, 
however, over when to implement the smoking cessation treatment: immediately (to present a consistent 
treatment message) or after a delay (to allow patients to stabilize on their SUD pharmacotherapy). Thus, 
researchers have called for more work to determine whether the timing of treatment integration affects 
outcomes for both smoking and SUDs. At WVU, the Comprehensive Opioid Addiction Treatment (COAT) 
program provides access to a relatively large population of opioid-dependent smokers in various stages of 
SUD treatment: Days 1 to 90 (weekly group), Days 91 to 180 (biweekly group), and Days 181 to >365 (monthly 
group). In the proposed study, all three groups will receive varenicline pharmacotherapy for 12 consecutive 


weeks. Study results will shed light on the feasibility of implementing smoking cessation therapy within the 
COAT clinic, results that may generalize to other treatment programs for opioid dependence. Results will also 
provide initial evidence for whether smoking cessation timing affects abstinence outcomes for both tobacco 
and opioid use. Such data are directly relevant to communities within the state of West Virginia, which are 
disproportionately affected by the harms of these drugs. Among all states, WV ranks 50th for tobacco use 
prevalence, as well as 49th for deaths related to recreational use of opioids (CDC, 2013). Ultimately, this line of 
work may lead to recommendations for improving outcomes associated with opioid dependence treatment, as 
well as improving outcomes for a population of smokers that may otherwise not quit tobacco. 
 
Probability of Group Assignment: Participants will be assigned to one of three groups based on duration of 
illicit-drug abstinence and time in COAT program. Groups will be assigned by the COAT program at the 
Chestnut Ridge Center and will be: 0 to 90 days abstinent (weekly group), 91 to 180 days abstinent (biweekly 
group), and 181 to ≥365 days abstinent (monthly group). All groups will receive the same varenicline treatment 
regimen per the label instructions. 
 
Inclusion criteria: Participants must report smoking >10 cigarettes per day for >1 year. An expired air CO 
reading of >10 parts/million (ppm) at screening will verify current tobacco use status. Individuals must also 
indicate interest in making a quit attempt in the next 1-6 months (Contemplation or Preparation stages), as 
measured via the Stage of Change (SOC; DiClemente et al., 1991). The SOC categorizes smokers into one of 
five stages: 1) no plans to quit (Precontemplation) 2) plans to quit in the next 6 months (Contemplation), 3) 
plans to quit in the next 30 days, with a recent attempt made (Preparation), 4) currently trying to quit (Action), 
and 5) have already quit (Maintenance). Individuals in the Precontemplation stage are likely too disinterested in 
quitting to consider the cessation program offered during the intervention, while individuals in the Action stage 
may have already begun changing their smoking behavior. Importantly, 70-90% of smokers are considering 
quitting but are not actively trying to quit (i.e., are in contemplation or preparation; Velicer et al., 1995). 
 
Exclusion criteria: Exclusion criteria include current engagement in any form of tobacco cessation (e.g., 
pharmacotherapy); current use of contraindicated medications (e.g., theophylline, warfarin, insulin, etc.); 
reports of smoking < 10 cigarettes per day; expired air CO < 10 ppm; Stage of Change category as 
Precontemplation (no plans to quit), Action (actively trying to quit), or Maintenance (have already quit); self-
reported seizures in the past year; untreated cardiovascular disease. Women will be excluded if they self-
report breast-feeding or are pregnant (verified by urinalysis).  
 
Justification for Equitable Enrollment of Subjects: No one will be excluded on the basis of gender, race, or 
ethnicity. 
 
Data/Safety Monitoring: The PI (Dr. Melissa Blank, Ph.D.) will be responsible for executing the Data and Safety 
Monitoring Plan (DSMP), and complying with all reporting requirements. 
 
Data Security:  All data (questionnaires, CO samples, tobacco use behavior) will be treated with professional 
standards of confidentiality. Data will be identified by code number only and stored on password-protected 
computers kept within locked rooms. Participants’ names are not directly associated with these data. The 
consent forms will be kept in the office of a PI (Dr. Blank), also in a locked cabinet. 
 
Safety Monitoring Plan: In the unlikely event of adverse event(s) during the conduct of the study described in 
this application, the laboratory has a mechanism in place to ensure that the event(s) will be reported to the IRB 
in a timely manner. The PI will report events that are unexpected and possibly, probably, or definitely related to 
study participation a) within 24 hours if they are fatal, life-threatening, or serious, and b) within 10 calendar 
days if they suggest greater risk of harm to study participant(s) than was previously known or unrecognized. 
 
How data will ensure safety for more than minimal risk: The inclusion/exclusion criteria ensure that we enroll 
only regular cigarettes smokers who are generally healthy.  That is, we will exclude individuals whose breath 
tests reveal that they are not smokers, and who report severe medical conditions (i.e., untreated 
cardiovascular disease, seizures). Once enrolled, participants will be given varenicline (an FDA-approved 
tobacco-cessation pharmacotherapy) for 12 weeks. Participants who experience intolerable side effects from 


the pharmacotherapy will have the freedom to stop use and withdraw from the study. For all participants, the 
health risks of study participation do not exceed those normally incurred in their own environment. 
 
Subjects: 
Participant Identification and Recruitment: Male and female smokers will be recruited from the Chestnut Ridge 
Center at WVU. Study enrollment will be open to any person who is enrolled in Comprehensive Opioid 
Addiction Treatment (COAT) at Chestnut Ridge Center for opioid dependence and is eligible based on 
screening procedures. 
 
Protection of WVU employees/students: WVU employees and students are not specifically targeted. However, 
these individuals may be included in the study if they are enrolled in COAT at Chestnut Ridge Center and are 
deemed eligible based on inclusion/exclusion criteria. Of course, they will be assured the same rights and 
protections as all other participants. Informed consent will be performed by a trained staff member and 
individuals will be informed of the voluntary nature of their participation. Their protection will be maintained by 
keeping the consent forms, which contain their full name, separate from all session data.  Specifically, consent 
forms will be kept in the office of the PI in a locked cabinet. Additionally, all computerized data will be stored on 
password-protected computers that are kept within a locked laboratory. 
 
Additional Provisions of WVU employees/students: WVU employees and students will be informed that their 
participation will in no way affect their status at WVU as an employee or student. Additionally, any participants 
who are current students of Dr. Blank will be assured that their participation will in no way affect their status in 
her class. As always, they will be able to withdraw from the study at any time without any adverse 
consequence. 
 
Consent Process (when, where, and how): Participants will be individuals enrolled in COAT at Chestnut Ridge 
Center at WVU. A trained member of our research team will visit Chestnut Ridge Center during regularly 
scheduled COAT meetings times for the informed consent process. Administration of the consent form will take 
place in a private room at the Chestnut Ridge Center by a trained staff member or co-investigator.   
 
Sample size: 
Justification: The sample size for this feasibility study is based on the estimated rate of attrition for the weekly 
group of COAT patients. The weekly group consists of those patients in the earliest stage of treatment, during 
which dropout rates would be greatest. The estimated dropout rate for this group is 20%. Thus, with 60 
participants (n=20/group: weekly, biweekly, and monthly) we would be able to estimate a compliance rate for 
intervention of 80% within + 10%. 
 
Management of information relevant to human subjects protection: Any unanticipated problems experienced 
during the course of the study or other interim results will be reported appropriately to the IRB within the 
approved timeline.  Moreover, as needed, interim results will be reported to participants prior to their enrollment 
into the study. Such interim results include any varenicline side effects that have not been commonly reported 
in the literature, including those outlined in the consent form (e.g., nausea, vomiting, sleep problems, and 
abnormal dreams). 
 
Potential Risks/Discomforts: 
Cigarette smokers who abstain from tobacco (i.e., those who choose to cut down or quit regular cigarettes) 
may experience an aversive withdrawal syndrome that includes irritability, restlessness, difficulty concentrating, 
hunger, and craving or urges to smoke. These effects can be uncomfortable but are not medically dangerous. 
These participants may also experience side effects reported of varenicline use: nausea, vomiting, sleep 
disturbance, abnormal dreams, gas, constipation. Notable is that these effects have been shown to dissipate 
with continued varenicline use, and do not appear to be significantly different from that incurred when using 
other nicotine replacement products like the patch (Bullen et al., 2013).  
 
Participants may also experience some discomfort when the nurse inserts or withdraws the needle, or when 
blood samples are taken. We try very hard to minimize patient discomfort at these times, and the use of a 
trained nurse and sterile, disposable equipment enhances comfort while reducing the risk of bruising and 
infection.  


 
Researcher interaction with participations kept private: Researchers will interact directly with participants in 
person. Individuals who are enrolled in the COAT program at Chestnut Ridge Center will be described the 
study requirements via the consent process.  At each contact, study staff will be sensitive to collecting only that 
information that the person voluntarily reveals. Additionally, both the screening and session visits will occur in 
one of the Chestnut Ridge Center session rooms, which can only be accessed by trained personnel and 
current patients. 
 
Potential Benefits to individuals: 
Research participants may significantly reduce or quit their use of regular cigarettes as a result of their 
participation in this study.  
 
Potential Benefits to Science/Society: This study has the potential to provide long-term benefits to society at 
large. Study results have the potential to reveal the influence of integrating smoking-cessation treatment with 
opioid-dependence treatment on abstinence outcomes of all substances. Given that tobacco and opioid use 
are significant problems in West Virginia, results form the current study may contribute to improved treatment 
packages for individuals with substance-use disorders. There is mixed evidence about when to integrate 
smoking cessation with substance-use disorder treatment. Specifically, we are interested in determining 
whether integrating smoking-cessation treatment at the beginning of opioid-dependence treatment, versus 
individuals are stabilized on opioid pharmacotherapy, will improve relapse rates for both substances. 
 
Consent Procedures: 
Why not PI or Co-I for conducting consent?: Co-investigators will be responsible for consenting participants. All 
staff will have passed the online CITI training modules, as well as will have completed additional training with 
the PI prior to working with participants. 
 
Confidentiality: 
How long will the data be kept? For participants that consent to participate, their screening and session data 
will be kept for no more than three years after the end of the study per recommendation of the American 
Psychological Association. 
 
Where will data be securely located? Consent forms will be kept in a locked cabinet in the office of the PI (Dr. 
Blank), separate from the data. Other data will be kept on password protected computers kept in locked rooms 
within the laboratory. Additionally, the laboratory is only accessible by key, and only the PI and her research 
assistants will hold a key. 
 
How will the data be destroyed? Hard copies of any forms (e.g., consent, screening documents, etc.) will be 
shredded, while electronic copies (e.g., session data) will be permanently deleted from any/all computers. 
 
How maintain confidentiality and privacy? Privacy interests will be protected by assigning codes to participants’ 
responses provided during screening and session visits. Names will not be associated with any of these data, 
and will be stored separately from consent forms that include participants’ signatures.  That is, consent forms 
will be kept in a locked file cabinet in the office of the PI (Dr. Blank), whereas screening and session data will 
be kept either in a locked file cabinet or on password protected computers located within session rooms in the 
laboratory. All data will be maintained for three years, as suggested by the American Psychological 
Association.  Access to participants will come from word-of-mouth or study advertisements (flyers or electronic 
announcements to the WVU and greater Morgantown community). 
 
Compensation: 
Payment distribution? For intervention visits, participants will receive payments in equal amounts: $100 each 
for visits 2, 3, and 4. Participants will not be paid during the initial screening visit. All compensation will be in 
the form of Visa gift cards, and the total amount possibly earned for completing the entire study will be $300. 
 
 


Statistical Analysis Plan 
 
Primary outcomes. The primary outcomes will be those relevant to feasibility: 1) recruitment rates (i.e., number 
of patients enrolled relative to the number of patients screened), 2) adherence to treatment components (i.e., 
proportion of participants who complete the varenicline regimen), 3) compliance with responding to text 
message-based questions (i.e., number of responses to text message-based questions out of the total number 
asked), and 4) overall retention rates (i.e., completion rates for entire treatment program). These outcomes will 
be examined via descriptive statistics.  
  
Secondary outcomes. Given that the proposed study is not powered to evaluate treatment efficacy, exploratory 
analyses will be employed to examine secondary outcomes. Using a one-way analysis of variance (ANOVA) 
groups will be compared on their proportion of relapses for all drugs, their proportion of smokers abstinent at 
each assessment, their average number of days until successful cigarette quit day, and their average ratings 
for tobacco withdrawal-related symptoms. Huynh-Feldt corrections will be used to adjust for violations of the 
sphericity assumption (Huynh & Feldt, 1976), and pairwise differences between means will be examined using 
Tukey’s Honestly Significant Difference (HSD; Keppel, 1991) correcting for multiple comparisons. Comparisons 
for which p<.05 will be reported as significant.  
 
Blood samples will be analyzed at the NIDA Center for Genetic Studies at Rutgers University.