Clinical trial NCT02698215
Conditions: Nicotine Dependence Alcohol Use Disorder
Sponsor: University of California, Los Angeles
Start date: 2016-05-01; Completion date: 2019-12-01
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a double-blind, randomized clinical trial using a two group medication design consisting of the combination of VAR (1 mg twice daily) + NTX (50 mg once daily) and VAR (1 mg twice daily) + PLA (matched to NTX), for smoking cessation in a sample of heavy drinking daily smokers who want to quit smoking and reduce drinking.

Detailed description:
This study is a double-blind, randomized clinical trial using a two group medication design consisting of the combination of VAR (1 mg twice daily) + NTX (50 mg once daily) and VAR (1 mg twice daily) + PLA (matched to NTX), for smoking cessation in a sample of heavy drinking daily smokers who want to quit smoking and reduce drinking. All participants will be daily smokers (≥ 5 cig/day) who are also heavy drinkers according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines: for men, \> 14 drinks per week or ≥ 5 drinks per occasion at least once per month over the past 12 months; for women, \> 7 drinks per week or ≥ 4 drinks per occasion at least once per month over the past 12 months. A total of 274 participants will be randomized, 137 to each medication group.

Arms: arm 1: VAR (1 mg twice daily) + NTX (50 mg once daily) arm 2: VAR (1 mg twice daily)
Interventions: intervention 1: Varenicline intervention 2: Varenicline plus Naltrexone
Intervention descriptions: intervention 1: Varenicline 1 mg twice daily intervention 2: Varenicline 1 mg twice daily plus Naltrexone 50 mg once daily

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Combining Varenicline and Naltrexone for Smoking Cessation and Drinking Reduction 
STUDY PROTOCOL 
Version 8.0, April 2018 
NCT02698215 
 
 
 


 
 
VAR-NTX for Smoking Cessation 
Protocol Version 8.0, April, 2018 
PI:  Lara Ray, PhD 
 
2 
 
 
STUDY PROTOCOL 
 
Combining Varenicline and Naltrexone for Smoking Cessation and Drinking Reduction  
 
 
1. INTRODUCTION 
 
 
This study addresses medication development for nicotine dependence and alcohol 
misuse, highly significant public health problems for which only modestly effective 
interventions are currently available. This study builds upon compelling preliminary data 
from the PI’s lab suggesting that the combination of varenicline and naltrexone may be 
superior to varenicline alone for heavy drinking smokers. The addition of naltrexone as 
an adjunct to varenicline seeks to break the link between higher smoking cessation 
relapse rates during drinking episodes [33, 103], which in turn may improve quit rates 
among this group of treatment-resistant smokers. Although naltrexone has been used 
as an adjunct to nicotine replacement therapy with some, although not uniform, benefit 
[79, 83-85, 87], to the best of our knowledge no clinical trials to date have combined 
varenicline and naltrexone. The study combines these two pharmacotherapies for a 
specific sub-group of smokers for whom heavy drinking represents an important risk 
factor for relapse in smoking cessation [7, 8]. This is a sizeable sub-group, representing 
at least 20-30% of all current smokers in the U.S. [3] and a group for whom the health 
consequences of smoking are exacerbated [4-6].  
 
An important challenge in the treatment of nicotine and alcohol dependence is the 
development of effective treatments for patients with special needs [90]. The present 
study addresses this challenge by testing a combination of pharmacotherapies for a 
special needs group of heavy drinking smokers. In addition, this study examines the 
effects of the combination pharmacotherapy on alcohol use, among smokers who are 
willing to reduce their drinking. This aim will elucidate the effects of this combination on 
heavy drinking, which in addition to posing an obstacle to smoking cessation 
exacerbates the negative health consequences from smoking. By comparing the 
combination to the field standard for alcohol misuse (i.e., naltrexone), this study will 
advance treatment development for alcohol use disorders. In brief, this study has the 
potential to inform treatments that can target two important public health concerns, 
namely smoking and drinking. The secondary aim is designed to inquire whether the 
effects of medication on alcohol craving and alcohol use mediate their clinical efficacy. 
This is significant as it would allow us to elucidate clinically meaningful mechanisms of 
action of varenicline, naltrexone, and their combination for the treatment of nicotine 
dependence and alcohol misuse.  
 
In summary, the significance of the study is high as it (a) addresses major public health 
concerns, namely nicotine dependence and alcohol misuse; (b) seeks to optimize 
treatment for a sizeable and treatment resistant sub-group of smokers, namely heavy 
drinking smokers; (c) builds upon a strong scientific rationale that encompasses both 
preclinical and clinical data on the co-use of nicotine and alcohol; (d) extends upon 


 
 
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compelling preliminary data supporting the combination of varenicline + naltrexone over 
monotherapy and placebo in the human laboratory; and (e) evaluates the effects of the 
combined pharmacotherapies on alcohol use outcomes in heavy drinkers who are 
willing to reduce their drinking, thereby informing treatment development for alcohol 
misuse. The successful completion of the study will inform clinical guidelines for the 
treatment of heavy drinking smokers, which currently consist simply of advising heavy 
drinking smokers to abstain from alcohol during their smoking quit attempt [19, 52]. 
Importantly, this study selects smokers who are motivated to change their drinking thus 
allowing for a meaningful evaluation of the combination of VAR + NTX for alcohol 
misuse, particularly in relation to the field standard for drinking (i.e., naltrexone alone). 
 
 
2. BACKGROUND AND SIGNIFICANCE 
 
2.1. Cigarette smoking and drinking: a bi-directional relationship  
 
Alcohol and cigarettes are two of the most widely abused substances and are often 
used in combination. It was recently estimated that 6 in 10 adults in the U.S. are current 
drinkers and 1 in 5 are current smokers [20]. Levels of alcohol use are higher in 
smokers than non-smokers, and the prevalence of smoking is higher in heavy drinkers 
compared to non-drinkers [3]. Almost 20% of current smokers engage in hazardous 
drinking, consuming 5 or more drinks on one occasion (4 or more for females) at least 
once per month [21, 22], compared to about 6.5% of nonsmokers [21]. Moreover, just 
over 55% of those with an alcohol use disorder smoke compared to 22.5% of lifetime 
alcohol abstainers [3]. A recent study found that 56% of tobacco quitline callers reported 
drinking and 23% reported hazardous drinking using NIAAA guidelines [4]. Of note, 
heavy drinking smokers experience more negative health consequences, including 
impairments in brain morphology and function [5] and greater risk for various cancers 
[6], than drinkers only and smokers only. 
 
Given the strong association between tobacco and alcohol use, researchers have 
attempted to elucidate the mechanisms underlying this relationship. In human laboratory 
studies, alcohol consumption is associated with increases in craving for cigarettes [23-
25], in a dose-dependent fashion [26, 27]. Interestingly, acute nicotine administration 
increased alcohol consumption among occasional smokers [28] while intranasal nicotine 
enhanced alcohol’s stimulant effects and attenuated its sedating effects [29]. More 
recently, a study has found that alcohol’s effect on craving for smoking was partially 
mediated by its positive association with the self-reported stimulant effects of alcohol 
[27]; thus increases in stimulation may account, in part, for alcohol’s effects on cigarette 
craving and smoking. In short, these studies highlight the complex, yet robust 
pharmacological interactions between alcohol and cigarettes.  
 
Alcohol may also increase the rewarding properties of smoking. Pretreatment with 
alcohol was found to increase enjoyment from smoking [30], increase satisfaction with 
smoking, potentiate the stimulant and calming effects of smoking, and relieve cigarette 
craving when individuals smoke nicotine-containing cigarettes compared to 


 
 
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denicotinized cigarettes [31, 32]. Alcohol also offsets some of the effects of the nicotine 
antagonist mecamylamine, which reduces satisfaction with smoking [32]. Of clinical 
importance, greater alcohol use is associated with decreased odds of smoking 
cessation [7, 8] and it is estimated that smokers are 4 times more likely to experience a 
smoking lapse during drinking episodes. A recent study of tobacco quitline callers found 
that hazardous drinkers had lower smoking cessation rates compared to moderate 
drinkers [4]. Given the co-occurrence of smoking and drinking and the neurobiological 
interactions between alcohol and nicotine, it has been convincingly argued that heavy 
drinking smokers constitute a distinct sub-population of smokers with a unique clinical 
profile and treatment needs [2, 9]. Although practice guidelines recommend smokers be 
advised to reduce or avoid drinking alcohol when making a quit attempt [19], there are 
no available pharmacological treatments or guidelines tailored to heavy drinking 
smokers, a sizeable and treatment-resistant sub-group. And while a recent behavioral 
treatment study found some support for incorporating a brief alcohol intervention to 
improve smoking cessation among heavy drinking smokers [33], no pharmacological 
studies to date have combined medications for smoking and drinking for this population. 
Thus, treatment development for heavy drinking smokers represents a highly significant 
and understudied research area. 
 
2.2. Varenicline:  effective for smoking cessation and may reduce alcohol use  
 
A number of pharmacological treatments have been developed for nicotine 
dependence.  Nicotine replacement therapy appears to be modestly effective, 
presumably by decreasing withdrawal [34]. Bupropion is another medication with 
moderate effectiveness, although its mechanisms of action remain relatively unclear. It 
is thought that the effect of bupropion on dopamine, noradrenaline, or even its direct 
effects on nicotine receptors may be involved in its clinical efficacy [35]. More recently, 
varenicline has been approved for the treatment of tobacco dependence. Molecular 
studies have convincingly demonstrated that the α4β2 subtype is necessary for nicotine 
dependence [36, 37]. Developed to address the critical role of α4β2 in tobacco 
dependence, varenicline is a partial agonist at α4β2 receptors. The putative 
mechanisms of action of varenicline stem from the stimulation of dopamine release (as 
a partial nicotine agonist) [38] and with its ability to block the binding of nicotine to its 
site (an antagonist effect), which in turn results in reductions in nicotine craving and 
reward [39]. At the behavioral level, varenicline-induced blockade of α4β2 nAChRs 
reduces craving and withdrawal and attenuates the rewarding effects of smoking [39-
43]. Functional neuroimaging studies found that varenicline increases activation of the 
dorsal anterior cingulate/medial frontal cortex, and dorsolateral prefrontal cortex during 
a working memory task [44] as well as during an emotional processing task [45]. 
Moreover, varenicline diminished smoking cue-elicited ventral striatum and medial 
orbitofrontal cortex responses compared to placebo [46]. Perhaps most importantly, a 
number of clinical trials found that varenicline is more effective than bupropion [10], 
superior to nicotine replacement therapy [47], and significantly more effective than 
placebo [10, 48-51] as a smoking cessation agent. As a result of this compelling clinical 
data, varenicline was advanced as a first line treatment for nicotine dependence [52]. It 
is to be noted, however, that abstinence rates on varenicline are about 43% at 12 


 
 
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weeks and 25% at one-year follow-up [53]. Thus, even though varenicline is superior to 
other treatments, there is a clear opportunity to improve upon these clinical outcomes, 
particularly among hard-to-treat sub-groups such as heavy drinking smokers. 
 
 
In addition to the effects of varenicline on smoking cessation, a number of studies have 
highlighted the role of the nicotinic acetylcholine receptor (nAChR) system in alcohol 
dependence phenotypes. Studies have suggested that alcohol produces mesolimbic 
activation through its effects on nAChRs [54-56]. Therefore, there is considerable 
enthusiasm for varenicline as a possible treatment for alcohol problems as well as the 
alcohol-nicotine co-abuse [2]. Preclinical studies have found that varenicline decreases 
ethanol self-administration in rats [57, 58]. Recent human studies of varenicline for 
alcohol use found that, compared to placebo, varenicline reduced alcohol self-
administration in the human laboratory [11], as well as alcohol craving [12] and alcohol 
consumption [12, 13] in smoking cessation trials. Interestingly, one study found that 
varenicline increased dysphoria and tended to reduce alcohol liking ratings following a 
controlled alcohol administration in the laboratory, suggesting that varenicline may 
potentiate the aversive effects of alcohol [59]. Together, these studies suggest that 
varenicline is an effective treatment for nicotine dependence and that it may have 
beneficial effects on alcohol use as well. Further, testing varenicline in combination with 
an alcoholism agent, such as naltrexone, may promote smoking cessation and drinking 
reductions over and above monotherapy. 
 
2.3. Naltrexone:  effective for alcohol problems and may improve smoking 
cessation outcomes 
 
Naltrexone is an opioid receptor antagonist with established efficacy, albeit moderate, 
for the treatment of alcohol problems. Shortly after two initial trials suggested that 
naltrexone resulted in significantly fewer drinking days and lower rates of relapse after 
three months of treatment [60, 61], naltrexone was regarded as one of the more 
promising pharmacological interventions for alcohol dependence [62]. These initial 
results have been largely supported by more recent trials of naltrexone that generally 
demonstrate beneficial effects on heavy drinking rates, particularly among those who 
are compliant with the medication [63-66].  Studies have found that naltrexone reduces 
the occurrence of heavy drinking days [64, 67, 68], increases time to first relapse [66, 
69, 70], yields lower relapse rates [60, 71, 72], reduces the number of drinking days [60, 
61], the number of drinks per drinking episode [61, 63, 65, 69], and the latency to first 
and second drink among social drinkers [73]. However, the support for naltrexone is not 
uniform. A few trials found no significant outcome differences between naltrexone and 
placebo treated-patients [74, 75]. Most recently, naltrexone was tested in the large, 
multi-site, COMBINE Study and was superior to placebo when delivered in combination 
with medical management [14], which advanced naltrexone as a first line of treatment 
for alcohol misuse.  
 
 
The neurobiological literature has recognized a role for the endogenous opioid system 
in modulating responses not only to alcohol, but to nicotine as well [76]. As such, 
naltrexone has been evaluated as a stand-alone as well as an adjunctive treatment to 


 
 
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smoking cessation. A study by O’Malley et al. found that naltrexone reduces drinking 
even among heavy drinking smokers who are not seeking treatment for alcohol 
problems [77] and similar results were recently reported by King and colleagues [78]. 
When naltrexone was used as an adjunct to smoking cessation, along with counseling 
and nicotine patches, naltrexone produced significantly higher quit rates than placebo 
but only at higher levels of depressive symptoms [79] or among females [80, 81]. While 
there is little support for naltrexone, and opioid antagonist broadly, as a stand-alone 
treatment for smoking cessation [82], studies found some support for the use of 
naltrexone as an adjunct to standard smoking cessation treatment, namely  bupropion 
and nicotine patch [83, 84], while one study did not support combining naltrexone with 
bupropion [85]. No clinical trials to date have tested the combination of VAR and NTX 
for smoking cessation in general, and for heavy drinking smokers, in particular. 
 
 
Although naltrexone is not an effective stand-alone treatment for smoking cessation, it is 
plausible that naltrexone may be a useful adjunct for a subgroup of smokers, particularly 
heavy drinking smokers. Results of laboratory studies have shown that naltrexone 
reduced cue-elicited withdrawal symptoms in combination with transdermal nicotine 
replacement [86] and that naltrexone alone attenuates smoking behavior [87] among 
heavy drinkers. Our own previous work with heavy drinking smokers revealed that 
naltrexone reduced urge to smoke during alcohol exposure [88]. Recent studies support 
the notion that naltrexone may be most useful in smoking cessation for a sub-group of 
patients who are heavy drinkers. In fact, a recent study found that naltrexone reduced 
drinking and improved smoking quit rates [15], particularly in heavy drinking smokers 
[16]. Interestingly, a re-analysis of the COMBINE Study found that naltrexone is more 
effective for the treatment of alcoholism in daily smokers than non-smokers [89]. In 
brief, there is no empirical support for naltrexone as a stand-alone treatment for nicotine 
dependence. However, results from recent human laboratory and clinical trials suggest 
that naltrexone may be effective among heavy drinking smokers trying to quit smoking. 
These studies, along with results from our recently completed human lab study testing 
the combination of naltrexone + varenicline on cigarette/alcohol reward and craving 
among heavy drinking smokers set the stage for testing this combination in a clinical 
trial. The rationale for adding naltrexone to varenicline for smoking cessation in heavy 
drinkers is based on the recognition that heavy drinkers are more prone to a smoking 
lapse during drinking episodes; hence a medication that helps patients reduce drinking 
may help them maintain smoking abstinence by preventing alcohol-related smoking 
lapses. 
 
2.4. Combining pharmacotherapies:  may optimize pharmacotherapy for 
smoking and drinking 
 
It has been increasingly recognized that complex biobehavioral problems such as 
nicotine dependence and alcohol misuse require novel and multifocal treatment 
approaches. The existing monotherapies for smoking, including varenicline, have shown 
moderate efficacy at best [53, 90]. The current study is based on the assertion that a 
combination of pharmacotherapies may be more effective at addressing the complex 
nature of tobacco dependence, particularly among this treatment-resistant group of 


 
 
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heavy drinking smokers. The selection of treatment combinations requires careful 
evaluation of the actions of the therapies to be combined [91]. Specifically, effective 
treatment combinations may be composed of two pharmacotherapies with mechanisms 
of action (both behavioral and neuropharmacological) thought to be compatible with one 
another, and potentially additive or synergistic. Based on the known pharmacological 
and behavioral effects of both naltrexone and varenicline, these medications show great 
promise for their combined use, particularly among the high-risk group comprised of 
heavy drinking daily smokers. In our preliminary laboratory work, we decided to study 
the combination of varenicline and naltrexone, as opposed to nicotine replacement or 
bupropion, because it specifically targets the α4β2 receptor and has proven to be the 
most effective pharmacotherapy currently available [92, 93]. The effects of varenicline 
are also relatively independent of those of naltrexone and there is no potential for 
negative drug interactions. Additionally, we chose naltrexone because it is the most 
effective FDA-approved pharmacotherapy for alcoholism developed to date and has 
been found effective even among smokers who are not seeking treatment for alcohol 
problems [83]. Studies have shown that naltrexone attenuates the reinforcing value of 
alcohol preventing the transition from a lapse into a full-blown relapse [66, 94]. Similarly, 
varenicline has been shown to disrupt the transition from smoking lapse to relapse [95]. 
Therefore, we hypothesize that the combination of varenicline and naltrexone will have 
additive effects on relapse prevention, particularly in drinking situations which are 
problematic for heavy drinking smokers [8]. Likewise, there appears to be a benefit of 
varenicline over placebo for drinking reduction. Specifically, a large RCT by Litten et al. 
(2013) found that the varenicline group had significantly lower weekly percent heavy 
drinking days (primary outcome), drinks per day, drinks per drinking day, and alcohol 
craving compared with the placebo group [96].Thus the combination of varenicline plus 
naltrexone holds great promise to attenuate heavy drinking, which was selected as the 
primary outcome in this study. 
 
 
Results from our human laboratory trial showed a benefit of combining varenicline and 
naltrexone on biobehavioral mechanisms of smoking relapse, namely cigarette craving 
and alcohol/smoking reward. We have argued that human laboratory studies serve an 
important role in medication development for addiction by allowing us to (a) screen 
promising medications, (b) identify doses, (c) elucidate mechanisms of action, and (d) 
test combined pharmacotherapies [97, 98]. Further, it is important to translate the 
mechanistic findings from human laboratory models by evaluating their clinical 
significance in smoking cessation outcomes [99-101]. Combining pharmacotherapies 
may offer significant advantages over monotherapies, such as permitting the use of 
lower doses of each component to achieve a given level of efficacy [102]. Lastly, 
combined treatments may facilitate tailoring of pharmacotherapies to the needs of 
individual patients, such as treatment augmentation in non-responders or patients with 
special needs (e.g., heavy drinkers, cancer patients, pregnant women) thereby 
addressing one of the challenges outlined by  Lerman and colleagues (2005) [90]. To 
that end, the present study seeks to address this challenge by testing a combination 
pharmacotherapy for heavy drinking smokers who want to quit smoking and reduce 
their drinking. 
 
 


 
 
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3. STUDY OBJECTIVES 
 
3.1. Primary Objectives 
 
The primary aims of this project are to test: 
 
  
(1a) Whether Varenicline (VAR) + Naltrexone (NTX) will result in higher rates of 7-day 
point prevalence smoking abstinence at 2, 4, 6, 8, 10, 12, 16, and 26 weeks post-quit 
date compared to VAR + Placebo (PLA). 
(1b) Whether VAR + NTX will result in lower drinks per drinking day at 2, 4, 6, 8, 10, 12, 
16, and 26 weeks post-quit date compared to VAR + PLA. 
 
3.2. Secondary Objective 
 
The secondary aim of this study is to test: 
 
(2a) Whether the effects VAR + NTX on smoking cessation outcomes and milestones 
are mediated by reductions in alcohol use, measured over the course of the trial. 
 
3.3. Supplemental Objectives 
 
The supplemental aims of this study are to test: 
 
(s1a) Whether men and women differ in reported side effects and treatment adherence 
(measured both by pill count and by study drop out) overall and between VAR + NTX 
and VAR only medication conditions. 
(s1b) Whether men and women differ on rates of 7-day point prevalence smoking 
abstinence at 2, 8, 12, 16, and 26 weeks post-quit date overall and between VAR + NTX 
and VAR only medication conditions. 
(s1c) Whether women and men differ in percentage of heavy drinking days at 2, 8, 12, 
16, and 26 weeks post-quit date overall and between VAR + NTX and VAR only 
medication conditions. 
(s2a) Whether E2 and P4 level, hormonal contraceptive use, and menstrual cycle phase 
at randomization and throughout the trial predict medication side effects and treatment 
adherence. 
(s2b) Whether E2 and P4 level, hormonal contraceptive use, and menstrual cycle 
phase at randomization and throughout the trial predict smoking abstinence and heavy 
drinking days. 
 
4. STUDY DESIGN 
 
This study is a double-blind, randomized clinical trial using a two group medication 
design consisting of the combination of VAR (1 mg twice daily) + NTX (50 mg once 
daily) and VAR (1 mg twice daily) + PLA (matched to NTX), for smoking cessation in a 
sample of heavy drinking daily smokers who want to quit smoking and reduce drinking. 


 
 
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All participants will be daily smokers (≥ 5 cig/day) who are also heavy drinkers 
according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines: 
for men, > 14 drinks per week or ≥ 5 drinks per occasion at least once per month over 
the past 12 months; for women, > 7 drinks per week or ≥ 4 drinks per occasion at least 
once per month over the past 12 months.  A total of 274 participants will be randomized, 
137 to each medication group.  
 
Interested individuals will come in to the laboratory for a two-part in-person screening 
visit. Eligible participants will then be randomized to either the combination of VAR (1 
mg twice daily) + NTX (50 mg once daily) or VAR (1 mg twice daily) + PLA. Medication 
will be titrated over a 14-day period. Participants will attend a brain imaging session and 
receive an individual counseling session during week 2 of the medication titration period 
and the quit date will be set for day 14 of the medication regimen. All participants will be 
instructed to continue the study medications for 12 more weeks (14 weeks total) and will 
return to the laboratory for follow-ups 2, 4, 6, 8, 10, 12, 16, and 26 weeks post quit date. 
Follow-up visits at weeks 2, 6 and 10 may take place over the telephone as needed.  At 
each follow-up, participants will complete questionnaires, receive brief smoking 
cessation counseling according to practice guidelines and will be encouraged to 
complete the online “Rethinking Drinking” program developed by NIAAA. Smoking 
abstinence [verified by CO level; 149] and alcohol use will be measured at each in-
person follow-up to test whether the combination of VAR + NTX is superior to 
monotherapy for smoking cessation and drinking reduction. 
 
4.1. Study Flow Diagram  
 
 
 
 
5. PHARMACOTHERAPY INTERVENTIONS 
 
5.1. Varenicline (VAR) 
 
Varenicline will be used in this study for oral administration in two strengths:  
• a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with 
"Pfizer" on one side and "CHX 0.5" on the other side 


 
 
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• a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on 
one side and "CHX 1.0" on the other side.  
Varenicline tablets will be provided by Pfizer and supplied in blister packs and should be 
stored at 77°F, with excursions permitted to 59–86°F. 
 
5.2. Naltrexone (NTX) 
 
NTX will be prepared by the UCLA pharmacy and packed into opaque capsules with 50 
mg of riboflavin (B2) to aid in medication compliance procedures.  Naltrexone will be 
provided for oral administration in three strengths: 
• 12.5 mg capsules will be provided for the first 3 days, packaged in a blister pack. 
• 25 mg capsules will be provided for days 4-7, packaged in a blister pack. 
• 50 mg capsules will be provided for weeks 2-14 in amber child-resistant 
medication bottles. 
 
5.3. Placebo (PLA) 
 
Placebo tablets will be prepared by the UCLA pharmacy and packed into opaque 
capsules with 50mg of riboflavin (B2) to assess for medication compliance.  Placebo 
capsules will be identical in appearance to Naltrexone tablets and will be provided in a 
blister pack for week 1 and in amber child-resistant medication bottles for weeks 2-14.   
 
 
5.4. Study Medication Blinding 
 
Naltrexone tablets and placebo tablets will be identically matched in appearance and 
the medication labels will not reveal the drug identity. The PI or designated approved 
study physician will make the decision to un-blind the identity of the study medication in 
the event that the study blind needs to be broken to make medical decisions regarding 
subject treatment (i.e. if necessary to assess AEs or SAEs for expedited reporting). 
Proper regulatory authorities will be notified if unblinding is required for a participant due 
to safety concerns. 
 
5.5. Study Medication Handling 
 
5.5.1. Medication Dispensing 
 
At the medication titration visit, study medication will be dispensed as prescribed by the 
study physician.  Drug accountability and compliance will be performed by the research 
staff at each clinic visit. The subject will be asked to bring all study medication and 
packaging (used and unused) to each subsequent visit for accountability. When study 
medications are dispensed, the subject will also be given a Medication Information 
Sheet for Varenicline and Naltrexone. 
 
5.5.2. Medication Accountability 
 


 
 
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The PI or designated study personnel will maintain a log of the receipt of all study 
medications and record of dispensing of all study medications to the subject. Medication 
for each subject will be inventoried and accounted for throughout the trial. The PI or 
designated staff will count the tablets remaining at the end of the study and record the 
tablet count on the appropriate drug accountability form. Subject compliance with 
medication will be assessed by comparing unused tablet count to dispensing logs and 
dosing records (number of tablets dispensed, number of tablets prescribed, versus the 
number returned). Subjects will also be asked to account for any missing tablets. If the 
medication is not returned, the subject will be asked to report daily drug self-
administration. 
 
5.5.3. Medication Compliance 
 
Pill counts will be conducted at each visit. In addition, the naltrexone study medication 
will be packed into opaque capsules with 50 mg of riboflavin (B2). A urine sample will be 
tested for riboflavin content by examining it under an ultraviolet light at each visit. In 
addition, 20% of all participants may be randomly selected for a serum verification of 
medication content (varenicline and naltrexone) at each follow-up. 
 
 
6. BEHAVIORAL INTERVENTIONS 
 
6.1. Initial Smoking Cessation Counseling Session 
 
All subjects will receive one smoking cessation counseling session to take place during 
week 2 of the medication protocol.  Per published guidelines, session will focus on 
problem solving and relapse prevention skills training. All study staff will be equipped to 
deliver this intervention through training and ongoing supervision by the PI, a licensed 
clinical psychologist. Subjects will be encouraged to maintain abstinence and to take the 
study medication. However, eligibility to continue in the study or receive study 
compensation will not be affected if participants do not maintain abstinence and/or are 
not compliant with the medication. This session will last approximately 45 minutes. 
 
6.2. Follow Up Smoking Cessation Counseling Sessions 
 
Participants will also receive brief cessation counseling at each follow-up visit focusing 
on topics as described above. 
   
6.3. Rethinking Drinking Program 
 
In addition, all participants will be encouraged to complete the “Rethinking Drinking” 
program online (http://rethinkingdrinking.niaaa.nih.gov/default.asp) while in the study 
and will discuss their drinking with the counselor. 
 
 


 
 
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7. STUDY PROCEDURES 
 
7.1. Recruitment of Subjects 
 
Mass media advertisements will be placed in local newspapers and on local radio 
stations in the greater Los Angeles metropolitan area. Targeted recruitment will also 
take place through existing research databases from the Ray and Leventhal 
laboratories (each laboratory has contact information for over 500 daily smokers who 
completed previous studies and are interested in being called about future studies) as 
well as through the UCLA primary care clinics. In addition, we will employ snowball 
sampling.  Participants who voluntarily agree will have an opportunity to forward a text 
message providing brief information about the study (drafted by the study team) to up to 
5 acquaintances.   Participants will earn an additional $1 in compensation for each text 
message they send, up to $5.  Men and women of all ethnic backgrounds will be 
recruited into the study. We expect that the study will reflect the ethnic diversity of Los 
Angeles County. Given that the requirement of ≥5 cig/day may disproportionally exclude 
females and ethnic minorities, targeted recruitment will be carried out to ensure a 
balanced representation of these groups in our study.  
 
 
7.2. Eligibility Criteria 
 
 
7.2.1. Inclusion Criteria 
 
To be included in the study, participants must:   
1. Be treatment-seeking for smoking cessation and have a desire to reduce or quit 
drinking 
2. Be between the ages of 21 and 65 
3. Be able to provide informed consent  
4. Smoke 5 or more cigarettes per day for the past year  
5. Currently drink heavily according to the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) guidelines: for men, > 14 drinks per week or ≥ 5 drinks per 
occasion at least once per month over the past 12 months; for women, > 7 drinks 
per week or ≥ 4 drinks per occasion at least once per month over the past 12 
months  
6. Pass the physical exam and associated laboratory tests, as determined by study 
physician. 
 
7.2.2. Exclusion Criteria 
 
To be included in the study, participants must not: 
 
1. Have clinically significant alcohol withdrawal, indicated by a score ≥ 10 on the 
Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) and assessed at the 
in-person screening visits 
2. Have lifetime DSM-V diagnosis of schizophrenia, bipolar disorder, a psychotic 
disorder, or any other psychiatric disorder as determined by the clinical interview 


 
 
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3. Have major depressive disorder within the past year requiring treatment as 
determined by the clinical interview using DSM-V criteria 
4. Have a current DSM-V diagnosis of a substance use disorder, other than for alcohol 
or nicotine, as determined by the clinical interview 
5. Have a prior history of taking FDA approved medications (i.e. varenicline or 
bupropion) for smoking cessation  
6. Be currently using any forms of nicotine replacement therapy (past use is 
acceptable) 
7. Have a serious medical illness (significant cardiovascular disease; uncontrolled 
hypertension; hepatic or renal disease) that would contraindicate participation, as 
determined by the study physician 
8. Be currently taking opioid pain medications or any form of opioid agonist 
maintenance therapy (such as methadone or buprenorphine) 
9. Be currently taking any psychoactive medications that would indicate serious or 
unstable mental illness, such as certain antidepressants, mood stabilizers or anti-
seizure medications, sedatives-hypnotics, anxiolytics, stimulants, antipsychotics, as 
determined by the study physician.  
10. Have self-reported use of cocaine, methamphetamine, heroin or other illicit drugs in 
the previous 60 days, verified by urine toxicology screen 
11. For women, must not be pregnant (as indicated by self-report or a positive 
pregnancy test at any study visit), nursing, or planning to become pregnant while 
taking part in the study, and must agree to one of the following methods of birth 
control, unless she or partner are surgically sterile: 
• 
Oral contraceptives 
• 
Contraceptive sponge 
• 
Patch 
• 
Double barrier 
• 
Intrauterine contraceptive device 
• 
Etonogestrel implant  
• 
Medroxyprogesterone acetate contraceptive injection 
• 
Complete abstinence from sexual intercourse 
• 
Hormonal vaginal contraceptive ring 
 
7.3. Screening Period 
 
7.3.1. Telephone Screen 
 
Individuals who call the lab (in response to flyers and advertisements) expressing 
interest in the study will receive detailed information about the study procedures, and if 
they remain interested they will complete a telephone screen performed by a trained 
research assistant for self-reported inclusion and exclusion criteria. Those who appear 
eligible will be invited to the laboratory for an initial in-person screening session.  
 
7.3.2. Initial Screening Visit 
 


 
 
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Prior to conducting any research related procedures, research staff will conduct the 
informed consent process which details the procedures to take place during the 
screening visit.  Informed consent will be a three part process.  First, participants will be 
asked to read and provide verbal consent for breathalyzer.   If the breathalyzer is above 
0.000, the visit will be stopped and the participant will not be compensated.  The 
participant will be given an opportunity to reschedule the visit for another day.  If the 
breathalyzer test is negative, the written informed consent form will be reviewed and 
signed by the participant and study staff outlining procedures for the initial screening 
visit.  A second written consent form will be reviewed and signed in the presence of the 
study physician at the medical screening visit if the participant is found eligible to 
continue to that visit.  
 
At the initial screening visit, subjects will be asked to provide a urine sample for cotinine 
verification of smoking status and test for drugs of abuse and pregnancy (if female), be 
given a breath test of CO level and will complete a series of smoking and individual 
differences measures (described in detail below). This visit should take 1.5 to 2 hours.  
 
Following the initial in-person screening, the study coordinator will meet with the PI to 
determine if the participant is eligible to continue to the medical screening based on 
study inclusion/exclusion criteria. 
 
7.3.3. Medical Screening Visit 
 
Those participants who appear to be eligible after the initial screening visit, will then be 
scheduled for a second screening visit to take place at the UCLA Clinical and 
Translational Research Center (CTRC). This visit will be conducted by the study 
physician and will start with a breathalyzer test. If the breathalyzer is above 0.000, the 
visit will be stopped and the participant will not be compensated.  The participant will be 
given an opportunity to reschedule the visit for another day.  If the breathalyzer test is 
negative, the physician will conduct the second written (experimental) consent, medical 
history interview, physical exam, Comprehensive Metabolic Panel including liver 
function tests (LFTs) and blood chemistry, and EKG to screen for medical conditions 
that contraindicate taking naltrexone and/or varenicline.  In addition, CO levels, and 
urine drug screen tests will be repeated. The study physician will review each 
participant’s medical history, vital signs, weight, review of systems, and laboratory tests, 
including liver function tests (LFTs), drug screen, chemistry screen, and urine 
pregnancy screen to determine if it is medically safe for the participant to take the study 
medication.  
 
Any subject who is excluded from the study will be compensated for their time in the 
screening session and will be offered referrals for smoking cessation treatment in the 
community. 
 
7.4. Medication Titration/Stabilization Period 
 
7.4.1. Randomization and Medication Titration Visit 
 


 
 
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Participants who are eligible after the medical screening visit will be scheduled to come 
into the lab to be randomized and start study medication.  Subjects will be urn 
randomized to one of two medication groups. Urn randomization will be used to balance 
the two medication groups by gender, number of cigarettes per day, and drinks per 
drinking day.  At this visit, a quit date will be set for day 14 of the medication 
titration/stabilization regimen. 
 
Female participants will be asked about their menstrual cycle and reproductive status 
and will answer questions about hormonal responses and symptoms (see Schedule of 
Assessments).  In addition, female participants of child-bearing potential will provide a 
saliva sample for testing of progesterone and estradiol levels and urine will be tested for 
surges in luteinizing hormone (LH).  
 
7.4.1.1. 
Medication Titration Schedule 
 
Titration 
Day 
VAR 
NTX/PLA 
1 
.5 mg once per day 
12.5 mg once per day 
2 
.5 mg once per day 
12.5 mg once per day 
3 
.5 mg once per day 
12.5 mg once per day 
4 
.5 mg twice per day 
25 mg once per day 
5 
.5 mg twice per day 
25 mg once per day 
6 
.5 mg twice per day 
25 mg once per day 
7 
.5 mg twice per day 
25 mg once per day 
8+ 
1 mg twice per day 
50 mg once per day 
 
All pills will be matched in number of pills and packaging across the two medication 
conditions (VAR + PLA and VAR + NTX). Participants will be asked to take the study 
medications for a period of 14 weeks and will complete regular follow-ups. 
 
7.4.2. Titration Follow Up Telephone Contact  
 
The study physician will contact the participant via telephone once during the first week 
of the medication titration period to assess for side effects/adverse events and the 
potential need for dosage adjustments.   
 
7.4.3. Initial Counseling Session 
 
All subjects will receive one smoking cessation counseling session to take place during 
week 2 of the medication titration period.  This session will last approximately 45 
minutes, and will focus on preparation for the upcoming quit date. 


 
 
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7.4.4. Brain Imaging Session 
 
Participants found to be eligible for an MRI, as determined by the MRI Safety Screening 
form, will be asked to complete a brain imaging session after 9-12 days of taking the 
medication. 
 
Participants will be asked to abstain from drinking alcohol prior to coming into the lab for 
the brain imaging session, which will be verified through a breathalyzer. Only 
participants with a blood alcohol concentration of zero will be allowed to complete the 
scanning visit. Female participants will be given a pregnancy test to make sure that they 
are not pregnant. We will also collect a urine sample on that day to verify compliance 
with the study medication. We will then ask participants to fill out a few questionnaires 
including information about your use of alcohol and tobacco.  
 
After the initial questionnaires, participants will receive some training on how to 
complete questionnaires in the scanner. The scanning will be performed at the Brain 
Mapping Center or at the Center for Cognitive Neuroscience, both located on the UCLA 
campus. They will be asked to lie down on a padded table, with their head placed in the 
center of a large, metal doughnut-shaped magnet.  While the machine is running, the 
participant will hear loud banging noises and will be offered earplugs to reduce the 
noise made by the magnet.  Head and back support will also be provided to minimize 
discomfort.  In the scanner, participants will watch brief videos of individuals smoking 
cigarettes or performing daily activities, such as driving And will view alcohol and neutral 
cues.  They will also be asked to rate their urge to smoke cigarettes and drink after 
watching each of these videos and visual cues. 
 
7.5. Medication Follow Up Period (Weeks 2, 4, 6, 8, 10, & 12) 
 
Follow-up visits will occur at the UCLA Addictions Lab on weeks 4, 8, 12, 16, and 26.  
Telephone or in-person follow-up interviews will be conducted at weeks 2, 6 and 10.  At 
each in-person follow up visit, participants will be asked to provide a urine specimen for 
cotinine level testing, perform an alcohol breathalyzer test, expired alveolar carbon 
monoxide (CO) levels test and complete measures as described in the Schedule of 
Assessments (Appendix 2).  In addition, urine specimen will be assessed for pregnancy 
and LH and saliva sample will be collected to test for progesterone and estradiol levels 
monthly for female participants.  Blood chemistry labs will be drawn at the last 
medication follow up visit at week 12. Participants will be asked to bring all study 
medication and used packaging to each visit to assess for medication compliance and 
will be dispensed study medication to last until the next scheduled visit.   
 
Female participants will be asked about their menstrual cycle and reproductive status 
and will answer questions about hormonal responses and symptoms (see Schedule of 
Assessments).  In addition, female participants of child-bearing potential will provide a 
saliva sample for testing of progesterone and estradiol levels and urine will be tested for 
surges in luteinizing hormone (LH). 


 
 
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7.6. Post-Medication Follow Up Period (Weeks 16 & 26) 
 
At 16 and 26 weeks post quit date, participants will return to the UCLA Addictions Lab 
for post-medication follow up visits.  At each visit, participants will be asked to provide a 
urine specimen for cotinine level testing, perform an alcohol breathalyzer test, expired 
alveolar carbon monoxide (CO) levels test and complete measures as described in the 
Schedule of Assessments (Appendix 2).  Female participants of child-bearing potential 
will also be tested for pregnancy, LH levels and progesterone and estradiol levels. 
 
 
 
 
7.7. Dose-adjustment Criteria 
 
Participants who discontinue study medication should still continue in the study, and 
complete all assessments as scheduled.  Females who become pregnant during the 
course of the study will be instructed to immediately discontinue use of the study 
medication and the pregnancy will be reported per required regulatory guidelines.  
Participants will need to be removed from study medication if they have a serious illness 
or a disabling condition that precludes them from taking the medication.  If the 
participant experiences any AEs that are considered study drug related and for which 
the study physician has determined that continuation of the study drug could be 
detrimental to the health of the subject, then drug will be immediately discontinued as 
described above. 
 
 
7.8. Subject Withdrawal or Discontinuation Procedures 
 
Participants have the right to withdraw consent and withdraw from the study at any time. 
In addition, the investigator may find it necessary to discontinue a participant for any 
reason, including the occurrence of an AE or noncompliance with the protocol. 
In the event that a participant withdraws or is discontinued from the study, the reason(s) 
for the discontinuation from the study will be recorded.  A final follow up visit will be 
scheduled and collected if possible. 
 
 
 
7.8.1. Stopping Criteria due to Safety Concerns 
 
The following trial stopping rules have been established: If two subjects have 
unexpected serious life-threatening AEs (attempted/completed suicide, extreme 
psychosis, etc.) the study will be halted and the DSMB will determine if the study should 
continue or be terminated overall.  
 
If at any time during study procedures, a participant develops any of the following 
stopping criteria, the study physician will abort study procedures, treat and/or observe 
the participant until stable, and discharge the patient from the study once stable with a 
14-day post-discharge outpatient follow-up visit to complete additional safety 
assessments: 
1. Abnormalities on liver function tests >3 times the baseline levels or any other 
clinically significant lab values or AEs. 


 
 
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2. Pregnancy: Both NTX and VAR are classified as Pregnancy Category C 
drugs by the FDA, and the drugs should only be used during pregnancy if the 
potential benefit justifies the potential risk to the fetus. As such, females who 
become pregnant during the course of the study will be instructed to 
discontinue the medication; the study physician will request a release of 
information to discuss the use study medication with their obstetrician. The 
participant will be followed through her pregnancy.    
3. Psychiatric crises, including but not limited to the following: 
a. Acute psychosis (hallucinations, impaired reality testing, paranoid ideation, 
etc.) requiring medication and/or hospitalization or intensive outpatient 
intervention; 
b. Suicidal or homicidal ideation that results in a credible threat of violence 
directed at oneself or others; 
c. Hospitalization for psychiatric symptoms 
4. A positive urine drug screen indicating illicit use of cocaine, 
methamphetamine, opiates, or other abused drugs at any visit during the trial. 
5. Self-reported use of contraindicated medications (as listed in the 
inclusion/exclusion criteria) 
 
Participants who report adverse reactions will be individually evaluated by the study 
physician. All participants will be clearly instructed that they may stop the study 
medication at any time. Upon physician evaluation, participants who reports either a 
severe side effect or any side effects that are not tolerable to them, whether severe or 
not, will be subjected to withdrawal by investigator and will be asked to discontinue the 
study medication immediately. In such cases, participants will be offered a follow-up 
visit with the study physician to re-evaluate symptoms upon discontinuation of the study 
medication. 
 
7.9. Compensation for Participation 
 
Participants will be compensated up to a total of $455 for their time and effort according 
to the following schedule: 
 
Initial screening visit:  
 
$20 
Medical screening visit:  
 
$20 
Medication Titration: 
 
$20 
Initial Counseling Visit: 
 
$20 
Brain Imaging Visit:  
 
$50 (if eligible) 
Follow up visit week 2:  
 
$20 
Follow up visit week 4: 
 
$20 
Follow up visit week 6: 
 
$20 
Follow up visit week 8:  
 
$20 
Follow up visit week 10: 
 
$20 
Follow up visit week 12:  
 
$50 
Follow up visit week 16:  
 
$50 


 
 
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Follow up visit week 26:  
 
$75 
Completion bonus week 26*: 
$50 
*Only participants who have completed all 12 study visits will be eligible to receive the $50 completion bonus. 
 
In addition, participants will have the opportunity to earn up to $5 additional at the initial 
screening visit for participating in snowball recruitment methods as described above. 
Participants who travel more than 10 miles from their home to attend visits on the UCLA 
campus will receive an additional $10 per visit to cover travel costs. All participants will 
be provided with free parking validation or bus tokens for attendance to each study visit. 
 
Female participants will receive an additional $10 at each of the following visits for 
completing female-specific study procedures as described above: Medication Titration, 
FU week 4, FU week 8, FU week 12, FU week 16 and FU week 26, totaling $410 for 
completion of all study procedures. 
 
Participants are free to discontinue participation at any time and will receive 
compensation for the amount of time that they participated.  
 
 
8. SAFETY MONITORING PLAN 
 
Safety monitoring will be conducted throughout the study; therefore safety concerns will 
be identified by continuous review of the data by the PI and study physician, internal 
quality assurance monitor, and DSMB. 
 
8.1. PI and Study Physician Safety Monitoring 
 
Participants will be given a 24-hour telephone number for calling the physician to 
discuss side effects, and physician office hours will be available as needed. Adverse 
events, including side effects will be collected in an open-ended way at each study visit. 
Vital signs, weight, and neuropsychiatric side effects, including depression and suicidal 
ideation, will be monitored at each study visit. The study physician will repeat all the 
clinical labs at the week 12 follow-up in order to verify that there were no changes 
associated with the 12-week medication regimen (+ 2 week titration/stabilization period). 
In the event that significant medical problems are encountered, the blind will be broken 
and appropriate medical treatment will be provided.  
 
8.2. Internal Quality Assurance Monitoring 
 
The PI will designate appropriately qualified personnel to periodically perform quality 
assurance checks at mutually convenient times during and after the study. These 
monitoring visits provide the opportunity to evaluate the progress of the study and to 
obtain information about potential problems. The monitor will assure that data are 
accurate and in agreement with any paper source documentation used, verify that 
subjects’ consent for study participation has been properly obtained and documented, 
confirm that research subjects entered into the study meet inclusion and exclusion 


 
 
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criteria, verify that study procedures are being conducted according to the protocol 
guidelines, monitor review AEs and SAEs, perform drug accountability, and assure that 
all essential documentation required by Good Clinical Practices (GCP) guidelines are 
appropriately filed.  At the end of the study, they will confirm that the site has the 
appropriate essential documents on file, advise on storage of study records, and inspect 
the return and destruction records for unused study medication. 
 
8.3. Data and Safety Monitoring Board (DSMB) 
 
An independent DSMB of external advisors will meet prior to the start of the study, bi-
annually during enrollment and follow-up and at trial end to review safety data. The 
Board will be blinded to subjects’ actual randomized group assignments but may 
request at any time that the blind be broken by the data center, if concerns arise from 
the blinded data. In addition to bi-annual meetings, the DSMB will meet after half of the 
subjects (137) have been randomized to review safety data and the integrity of the 
study (i.e., an evaluation of the dropout rate and impact on the planned statistical 
analysis of the data) and make a formal recommendation to the PI on the continuation 
or early stopping of the study due to safety concerns. Ad hoc meetings will be convened 
if SAEs occur that are considered at least possibly related to the study medication. 
 
9. ASSESSMENTS 
 
All study assessments will be performed at the visits and time points outlined in the 
Schedule of Assessments (Appendix 2); the following sections outline the details and 
procedures associated with the assessments. Most assessments will be recorded 
directly into the EDC system (MediaLab) with the exception of a few, which will be 
completed first on paper, then entered into the database as noted below. 
 
 
9.1. Adverse Events (AE) and Serious Adverse Events (SAE) 
 
The study physician and study site staff are responsible for the detection, 
documentation, classification, reporting, and follow up of events meeting the definition of 
an AE or SAE.  Adverse Events will be assessed at the medical screening visit and at 
each subsequent visit through the week 26 follow up visit.  However, SAEs will be 
collected from the time of informed consent onward. General symptoms will be collected 
via an open ended question: “How have you been feeling since your last visit or the last 
time we spoke?” 
 
Adverse Events will be recorded on the AE Log using accepted medical terms and/or 
the diagnoses that accurately characterize the event. When a diagnosis is known, the 
AE term recorded on the eCRF will be the diagnosis rather than a constellation of 
symptoms. The study physician will assess all AEs for seriousness, relationship to study 
medication, and severity. When an event has not resolved by study closure, it will be 
documented on the AE Log as “ongoing”. 
 


 
 
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If a woman has a positive or borderline pregnancy test after enrollment, the pregnancy 
will be recorded as an AE. The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been terminated or completed. 
The outcome of the pregnancy (e.g., normal birth, death, abortion, congenital anomaly, 
or other disabling or life-threatening complication to the mother or newborn) will be 
recorded. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed by study physicians until satisfactory resolution 
(the event either resolved or stabilized and is not expected to resolve in the near term).  
All SAE’s will be reported per requirements.  
 
9.1.1. Adverse Event (AE) Definition 
 
An AE is any untoward medical occurrence in a participant who has been administered 
a pharmaceutical product and may not necessarily have a causal relationship with the 
administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality), symptom, or disease 
temporally associated with the use of the study medication, whether or not related to the 
medication. Pre-existing conditions, diseases, or disorders are not considered AEs 
unless there is a change in severity or frequency. 
 
9.1.1.1. 
Classification of Adverse Event Intensity and Relationship to Study 
Medication 
 
For each recorded AE or SAE, the physician must make an assessment of severity 
based on the following criteria: 
 
• Mild: An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
• Moderate: An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. The 
event is usually ameliorated with additional specific therapeutic intervention. 
• Severe: An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the subject 
and hospitalization may be required, and typically requires intensive therapeutic 
intervention. 
• Life-threatening: An event that puts the subject into imminent risk of death 
without intervention. 
 
The physician must also make an assessment of relationship to the investigational 
product based on the following criteria: 
• Unrelated: The subject did not receive the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is not reasonable, or there is another obvious cause of the AE/SAE. 


 
 
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• Unlikely: There is evidence of exposure to the investigational product but there 
is another more likely cause of the AE/SAE. 
• Possible: There is evidence of exposure to the investigational product, the 
temporal sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, but the AE/SAE could have been due to 
another equally likely cause. 
• Probable: There is evidence of exposure to the investigational product, the 
temporal sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, and the AE/SAE is more likely explained by 
the investigational product than by any other cause. 
• Definite There is evidence of exposure to the investigational product, the 
temporal sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 
 
9.1.1.2. 
Outcomes and Actions Taken 
 
All unresolved AEs will be followed for a minimum of 14 days (unless the AE is an 
ongoing pregnancy which must be followed to conclusion) after the subject’s final study 
visit, unless the investigator’s judgment dictates otherwise, the event has resolved or 
stabilized prior to the 14-day period, or the subject is lost to follow-up. Investigators are 
not obligated to actively seek AEs or SAEs in former study subjects that occur following 
the follow-up period. 
 
For each recorded AE or SAE, the investigator must make an assessment of outcome 
at the time of last observation, as follows: 
 
• Fatal: The subject died. 
• Resolved without Sequelae: The AE or SAE has ended. 
• Resolved with Sequelae: The AE or SAE has ended but changes are noted 
from baseline. 
• Unresolved – Ongoing: The AE has not ended and is ongoing at the end of the 
reporting period (i.e., 14 days after the final Follow-up visit) and the investigator 
deems that further follow up is not medically required 
• Unknown – Lost to Follow-up: Lost to follow-up after repeated unsuccessful 
attempts to contact the subject. 
 
Actions taken with respect to study medication (discontinuation or not) will also be 
recorded. In addition, if the AE was treated (medications or other physical measures), 
this will also be recorded. 
 
9.1.2. Serious Adverse Event (SAE) Definition 
 


 
 
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An SAE is any untoward medical occurrence that meets one of the following: 
• Results in death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or 
frequency in the risk information included in the Product Label for the drug. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the study subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definition. 
 
9.2. Alcohol Consumption Questionnaire (ACQ)  
 
The Alcohol Consumption Questionnaire is measured with nine items assessing lifetime 
drinking history such as current drinking, age of onset, and attempts to quit/reduce 
drinking.  This assessment will be completed directly by the participant at the initial 
screening visit. 
 
9.3. Alcohol Use Disorders Identification Test (AUDIT) 
 
The Alcohol Use Disorders Identification Test is used to identify persons with hazardous 
and harmful patterns of alcohol consumption. The AUDIT was developed by the World 
Health Organization (WHO) as a simple method of screening for excessive drinking.  
The AUDIT is a self-report measure that will be completed by the participant in 
MediaLab at the initial screening visit. 
 
9.4. Barratt Impulsivity Scale (BIS-11) 
 
The BIS-11 is a widely used measure of impulsiveness that includes 30 self-reported 
items that are scored to yield six first-order factors (attention, motor, self-control, 
cognitive complexity, perseverance, and cognitive instability impulsiveness) and three 
second-order factors (attentional, motor, and non-planning impulsiveness). This 
questionnaire will be completed by the participant electronically during screening and at 
each follow up visit. 
 
9.5. Breathalyzer 
 
An alcohol breathalyzer will be administered at consent, and at every in-clinic visit as a 
safety measure. BrAC must be equal to 0.000 prior to performing any study 
assessments.  Results will be recorded on the paper checklist, and later entered into the 
database. 
 
9.6. Clinical Laboratory Tests 


 
 
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Clinical laboratory tests, including a chemistry panel and liver function tests, will be 
performed at CTRC during the medical screening and week 12 follow up visits.  The 
total blood volume to be collected is approximately 72 mL. Additional laboratory 
samples may be taken at the discretion of the study physician if the results of any tests 
fall outside reference ranges or clinical symptoms necessitate testing to ensure safety.  
 
9.7. Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) 
 
The CIWA-AR is a brief 10-item measure used to provide a quantitative index of the 
severity of the alcohol withdrawal syndrome. The CIWA-AR has been used both in 
clinical and research applications and has demonstrated both reliability and validity.  
This questionnaire will be administered on paper by appropriately trained staff during 
screening, at the medication titration visit, and at each follow-up visit.  Participant 
responses will then be entered electronically. 
 
9.8. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of 
ideation, and suicidal behavior developed by Posner and collaborators at the New York 
State Psychiatric Institute. This scale is intended for use by trained administrators. The 
questions contained in the C-SSRS are suggested probes. Ultimately, the determination 
of the presence of suicidality depends on clinical judgment. Training is required before 
administering the C-SSRS through a 30-minute interactive slide presentation followed 
by a question-answer session through the Columbia University Medical Center. Those 
completing the training are certified to administer the C-SSRS, and will receive a 
training certificate. This scale will be used to assess current suicidal ideation at 
screening and at each follow up visit and will be administered by a trained staff member 
with responses recorded on paper first, then entered electronically. 
 
9.9. Concomitant Medications 
 
All medications taken by the participant 2-weeks prior to the start of screening and 
through the final follow-up contact at week 26 will be recorded. All medications reported 
by the participant will be recorded on a source document and later entered 
electronically. 
 
9.10. 
Demographics 
 
Demographics data include the participant’s age, gender, race/ethnicity, marital status, 
education, employment pattern, occupation, and income level. These data will be 
collected by site staff at the initial screening visit on a source document and entered into 
an eCRF. 
   
9.11. 
Drug Use Questionnaire (DUQ) 
 


 
 
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The Drug Use Questionnaire will collect information on frequency and quantity of drug 
use.  Participants will directly enter responses into MediaLab at the initial screening 
visit. 
 
9.12. 
Eating Disorders Inventory (EDI) 
 
The EDI (Gerner, 1991) will be completed by all participants at the initial screening visit 
to assess for general weight concerns.  Participants will directly enter responses into 
MediaLab. 
 
9.13. 
EKG 
 
A 12-lead resting ECG will be obtained at the medical screening visit. Any abnormalities 
will be noted and an assessment of clinical significance will be done by the study 
physician. 
 
 
 
9.14. 
Alveolar Carbon Monoxide (CO) Levels 
 
A Vitalograph CO monitor will be used to detect CO levels at screening to verify that 
participants are regular smokers and at follow up visits to assess for smoking 
abstinence.  Test results will be recorded on the visit checklist and then entered into the 
database.  
 
9.15. 
Fagerström Test for Nicotine Dependence (FTND) 
 
The Fagerström Test for Nicotine Dependence will be used to assess smoking status 
and motivation to change smoking behavior at screening. This questionnaire will be 
completed by the subject electronically. 
 
9.16. 
Family Tree Questionnaire (FTQ) 
 
Information on family history of alcohol problems will becollected using the Family 
Tree Questionnaire. The questionnaire provides subjects with a family tree listing of 
relatives to identify blood relatives with alcohol problems. This questionnaire will be 
completed by the subject electronically at the initial screening visit. 
 
9.17. 
Hospital Anxiety and Depression Scale (HADS) 
 
The Hospital Anxiety and Depression Scale is a self-assessment tool to assess anxiety 
and depression levels.  This measure will be completed at the initial screening visit and 
entered with participant responses entered directly into the database. 
 
9.18. 
ImBIBe 
 


 
 
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ImBIBe is a 15-item questionnaire in which the subject responds on a 5-point scale 
responses to questions on the consequences of alcohol use. This scale was adapted 
from the Drinker Inventory of Consequences (Drinc) questionnaire based on FDA 
recommendations on patient reported outcomes. This questionnaire will be completed 
by the participant electronically. 
 
9.19. 
Medical History 
 
A Medical History interview will be conducted by the study physician at the medical 
screening visit and will screen for medical conditions that contraindicate taking 
naltrexone and/or varenicline.   
 
9.20. 
Menstrual Cycle Calendar 
 
The Menstrual Cycle Calendar (Roche and King, 2015) is a calendar-based interview 
will estimate recent dates of menstruation, determine average menstrual cycle length, 
and estimate the onset of next menses. It will be administered to female participants at 
the medication-titration visit and follow-up visits at week 4, 8, 12, 16 and 26. 
 
9.21. 
Menstrual Distress Questionnaire (MDQ) 
 
The MDQ (Moos, 1968) will assess the level of menstrual cycle distress female 
participants of child-bearing potential experienced during their most recent cycle.  This 
questionnaire will be completed by female participants at the medication titration visit, 
and at the week 4, week 8, week 12, week 16 and week 2 follow-up visits. 
 
9.22. 
Minnesota Nicotine Withdrawal Scale (MNWS) 
 
The Minnesota Nicotine Withdrawal Scale assesses signs and symptoms of nicotine 
withdrawal.  The participant will respond to this 9-item assessment at the initial 
screening visit and all follow up visits.   
 
9.23. 
Morisky Medication Adherence Questionnaire (MAQ) 
 
The Morisky Medication Adherence Scale (MMAS) is a generic self-reported, 
medication-taking behavior scale, validated for hypertension but used for a wide variety 
of medical conditions.  It consists of four items with a scoring scheme of “Yes” = 0 and 
“No” = 1.  The items are summed to give a range of scores from low adherence to high 
adherence.  This measure will be completed by the participant at the initial screening 
visit and at each of the medication follow up visits.  
 
9.24. 
Opioid Receptor Antagonist Scale 
 
Women will complete an opioid receptor antagonist-specific adverse effect scale that 
has been previously shown to be related to menstrual cycle related distress and 


 
 
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response to naltrexone (Epstein and King 2004; Roche et al., 2015).  This measure will 
be completed at the medication titration, week 4, 8, 12, 16 and 26 visits. 
 
9.25. 
Ovulation Predictor Test 
 
A one step ovulation urine test will be used to determine when there is a surge in the 
(LH) luteinizing hormone, which will inform where female participants are in their 
menstrual cycle.  This measure will be completed at the medication titration, week 4, 8, 
12, 16 and 26 visits. 
 
9.26. 
Penn Alcohol Craving Scale (PACS) 
 
The PACS is a five-item, self-report measure that includes questions about the 
frequency, intensity, and duration of craving, the ability to resist drinking, and asks for 
an overall rating of craving for alcohol for the previous week. Each question is scaled 
from 0 to 6.  Participants will complete this scale at initial screening and at each follow 
up visit. 
 
 
9.27. 
Physical Exam 
 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, 
cardiovascular system, lungs, abdomen, extremities, skin, neuropsychiatric mental 
status and sensory/motor status, musculoskeletal system and general appearance will 
be performed during the medical screening visit.  Abnormal findings will be reported as 
AEs, if appropriate. 
 
9.28. 
Positive and Negative Affect Scale (PANAS) 
 
The Positive and Negative Affect Scale comprises two mood scales, one that measures 
positive affect and the other which measures negative affect.  The scale consists of 20 
items using a 5-point scale that ranges from very slightly or not at all (1) to extremely 
(5).  Participants will completed the PANAS initial screening and all follow up visits. 
 
9.29. 
Pregnancy and Birth Control Assessment 
 
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test).  If 
applicable, participants will be asked to sign a release of information form for study 
personnel to access medical records to obtain information regarding the outcome of a 
pregnancy that occurred during the study.  The Birth Control Assessment is designed to 
determine a female subject’s compliance with the birth control specifications detailed in 
the inclusion criteria.  The Pregnancy and Birth Control Assessment will be completed 
at the initial screening visit, the medication titration visit, and at the 4, 8 and 12 week 
follow up visits.   
 
9.30. 
Questionnaire of Smoking Urges – Brief (QSU-Brief) 


 
 
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The Brief Questionnaire of Smoking Urges (QSU-Brief) consists of ten statements 
regarding the respondent's desire to smoke cigarettes at the time of assessment (i.e 
now). This ten item questionnaire measures agreement or disagreement with each 
statement by means of a 7-point scale where '1' indicates "strongly disagree" and '7' 
indicates "strongly agree." This assessment takes less than two minutes to administer 
and will be utilized at screening and all follow-up visits. 
 
9.31. 
Readiness to Change (RTC) Ladder (cigarette use/alcohol use) 
 
The Readiness to Change Ladder is a measure with 11 response items designed to 
assess motivation to reduce or cut back on smoking and drinking.  This assessment will 
be completed at the initial screening visit.   
 
9.32. 
Saliva Collection 
 
Normally-cycling and hormonal contraceptive using women will provide saliva samples 
for hormonal testing at medication titration and on each return to the laboratory for 
follow-ups 4, 8, 12, 16 and 26 weeks post quit date.  Self-reported menstrual cycle 
phase will be confirmed by measuring levels of estradiol (E2) and progesterone (P4). 
 
9.33. 
Self-Reported Habit Index Form (cigarette use/alcohol use) 
 
The Self-Reported Habit Index Form is a 12-item index of habit strength for cigarette 
and alcohol use that will be completed at the initial screening visit.  Responses will be 
self-reported by participants directly into the electronic data capture system.     
 
9.34. 
Smoking History Questionnaire (SHQ) 
 
The Smoking History Questionnaire will collect information on frequency and quantity of 
nicotine use.  Participants will directly enter responses into the EDC system at the initial 
screening visit.   
 
9.35. 
Structured Clinical Interview (SCID) 
 
The SCID is a semi-structured interview for making the major DSM Axis-I diagnoses.  It 
will be assessed by appropriately trained research staff to all participants at the initial 
screening visit to determine alcohol use disorder and rule out other exclusionary 
diagnoses.  
 
9.36. 
30-day Timeline Followback (TLFB) 
 
The Time Line Follow Back will be administered for both alcohol use and cigarette 
smoking at initial screening, medication titration, and at all follow up visits. Information 
obtained in this interview will be recorded on the TLFB Calendar and transcribed to the 
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9.37. 
Urine Cotinine Levels 
 
Participants will be asked to provide a urine specimen at the initial screening visit for 
testing of cotinine levels to verify that the participant is a regular smoker and at all follow 
up visits to assess for smoking abstinence.   
 
9.38. 
Urine Drug Screen 
 
An FDA cleared, CLIA waived urine drug test card will be used at the initial screening, 
medical screening and medication titration visits to assess candidates for recent use of 
opioids, cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone 
or benzodiazepines. Subjects must be negative for all substances except THC.  Results 
will be recorded on the visit checklist first and then entered into the database. 
 
9.39. 
Vital Signs 
 
Vital signs assessed at each visit include sitting blood pressure and pulse rate (after 
sitting for at least 3 minutes) and weight.  Values will be recorded on the visit checklist 
and entered into the database. 
 
9.40. 
Wisconsin Inventory of Smoking Dependence Motives (WISDM) 
 
The Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) assesses 13 
varied smoking motives in order to assess processes that may lead to nicotine 
dependence.  Responses to this measure will be directly entered by the participant at 
the initial screening visit.   
 
9.41. 
Wisconsin Predicting Patient’s Relapse (WI-PREPARE) 
 
The Wisconsin Predicting Patient’s Relapse is a brief, seven-item questionnaire that 
taps physical dependence, environmental factors, and individual difference 
characteristics to suggest the nature of a patient's short- and medium-term relapse risk.  
The WI-PREPARE will be assessed at the initial screening visit with direct data entry by 
the participant.  
 
9.42. 
Yale Craving Scale (YCS) 
 
The Yale Craving Scale will be used to assess smoking and drinking urges at initial 
screening.  This measure utilizes a generalized Labeled Magnitude Scale, which will be 
assessed by participants on paper and later scored and entered into the database.   
 
 
10. ETHICS  
 
10.1. 
IRB Review  


 
 
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The study will be conducted under a protocol reviewed by the UCLA IRB; the study is to 
be conducted by scientifically and medically qualified persons; the benefits of the study 
are in proportion to the risks; the rights and welfare of the subjects will be respected; the 
physicians conducting the study will ensure that the hazards do not outweigh the 
potential benefits; the results to be reported will be accurate; subjects will give their 
informed consent and will be competent to do so and not under duress; and all study 
staff will comply with the ethical principles in 21 Code of Federal Regulations (CFR) Part 
50 and the Belmont Principles. 
 
10.1.1. 
Protocol Modifications 
 
All necessary protocol changes will be submitted in writing as protocol amendments to 
the IRB by the PI for approval prior to implementation.  
 
 
10.1.2. 
Protocol Deviation Reporting Procedures 
 
All subject-specific deviations from the protocol are to be documented. The PI or 
designee will be responsible for identifying and reporting all deviations, which are 
occurrences involving a procedure that did not follow the study protocol. Any protocol 
deviation that adversely affects the safety or rights of a subject or scientific integrity of 
the study is considered a major deviation and will be reported immediately to the UCLA 
IRB. 
 
 
10.2. 
Ethical Conduct of the Study 
 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, 
beneficence, and justice. 
 
The procedures set out in this study are designed to ensure that all study personnel 
abide by the principles of the ICH GCP Guideline and the Code of Federal 
Regulations (CFR). The PI confirms this by signing FDA Form 1572. 
 
 
10.2.1. 
Confidentiality of Data and Subject Records 
 
 
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports and other 
records will be identified by a subject number only. Research and clinical records will be 
stored in a locked cabinet. Only research staff, sponsor officials, and other required 
regulatory representatives will have access to the records. Subject information will not 
be released without written permission. The PI has received a Certificate of 
Confidentiality for this study. 
 
 
10.2.2. 
Compensation for Participation 
 
 


 
 
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Subjects will be compensated for travel expenses and for time contributed to this 
research study in the form of cash. Compensation will be provided at each subject visit 
and is detailed in the informed consent form. 
 
10.2.3. 
Written Informed Consent  
 
The informed consent process and document will be reviewed and approved by the IRB 
and prior to initiation of the study. The consent document contains a full explanation of 
the possible risks, advantages, and alternate treatment options, and availability of 
treatment in the case of injury, in accordance with 21 CFR Part 50. The consent 
document indicates that by signature, the subject, permits access to relevant medical 
records as described above. A written informed consent document, in compliance with 
21 CFR Part 50, 32 CFR Part 219, and the Belmont Principles, and HIPAA 
Authorization will be signed by the subject before any study-related procedures are 
initiated for each subject. All potential subjects for the study will be given a current copy 
of the Informed Consent Form to read. All aspects of the study and informed consent 
will be explained in lay language to the subject by either the investigator, or a medically 
trained designee. Any subject who is unable to demonstrate understanding of the 
information contained in the informed consent will be excluded from study participation. 
All study subjects will be given a copy of the signed informed consent. 
 
10.2.4. 
Delegation of Responsibilities and Adequate Resources 
 
 
The PI should have adequate time to conduct the study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study. 
The term “investigator” used throughout this protocol refers to the PI and/or qualified 
Sub-investigators. The PI may delegate responsibilities to other study site personnel. 
The PI shall delegate tasks only to individuals qualified by education, training, and 
experience to perform the delegated tasks. The PI shall have direct oversight of all 
delegated activities and shall document delegation of responsibilities. The PI is 
responsible for ensuring all delegated staff has been properly trained on the protocol 
and their assigned study responsibilities. A delegation log identifying all delegated 
duties and the individual to whom they have been delegated will be maintained at the 
study site. 
 
10.2.5. 
Financial Disclosure 
 
Clinical investigators are required to provide financial disclosure information for the 
submission of certification or disclosure statements required under 21 CFR § 54. As 
defined in 21 CFR §54.2, a clinical investigator is a listed or identified investigator or 
sub-investigator who is directly involved in the treatment or evaluation of research 
subjects. The term also includes the spouse and each dependent child of the 
investigator. In addition, investigators must promptly update financial disclosure 
information if any relevant changes occur during the course of the investigation and for 
1 year following completion of the study. 
 


 
 
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11. DATA HANDLING AND RECORD KEEPING 
 
Source documents include but are not limited to original documents, data and records 
such as hospital/medical records (including electronic health records), clinic charts, 
laboratory results, data recorded in automated instruments, and pharmacy records, etc. 
This study will use an electronic data capture (EDC) eCRF system (MediaLab) and 
paper source documents. Data will be transcribed from source documentation directly 
into a statistical program such as SPSS. Only questionnaire data will be entered directly 
into eCRF (i.e., without prior written or electronic record of data). Paper copies of the 
eCRFs will be available in the event that the EDC is not accessible at the time the 
questionnaire is being completed. The transcribed data will be consistent with the 
source documents or the discrepancies will be explained.  All entries, corrections, and 
alterations will be made by the investigator or other authorized study personnel.  The 
EDC system maintains a full audit trail of data entry, data corrections, and data queries.  
 
11.1. 
Subject Identification and Confidentiality 
 
 
Subjects will be identified on eCRFs and paper source documents by a unique subject 
number. No personal identifier will be used in any publication or communication used to 
support this research study. The subject number will be used if it becomes necessary to 
identify data specific to a single subject. Regulatory bodies, such as the study sponsor, 
National Institute of Drug Abuse (NIDA), FDA, IRB, and the FDA are eligible to review 
medical and research records related to this study as a part of their responsibility to 
protect human subjects in clinical research. Personal identifiers will be removed from 
photocopied or electronic medical and research records. 
 
11.2. 
Retention of Records 
 
The investigator is responsible for creating and/or maintaining all study documentation 
required by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, 
ICH E6 section 8, as well as any other documentation defined in the protocol. The 
investigator must provide key documents to the Sponsor prior to start of the study. 
Federal and local regulations require that the investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the 
following is the longest period of time: 
• 
A period of 2 years following the final date of approval by the FDA or other 
regulatory agency of the study drug for the purposes that were the subject of the 
investigation; or 
• 
A period of 5 years following the date on which the results of the investigation 
were submitted to the FDA or other regulatory agency in support of, or as part of, 
an application for a research or marketing permit for the study drug for the 
purposes that were the subject of the investigation. 
If the investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 


 
 
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address of the new custodian. Study records should not be destroyed without 
consultation with the Sponsor. 
 
 
11.3. 
Trial Registration 
 
The PI will register the trial on the National Library of Medicine’s Clinical Trials Registry 
at http://www.clinicaltrials.gov. 
 
 


 
 
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13. APPENDICES  
13.1. 
Appendix 1:  Schema of Study Procedures 
13.2. 
Appendix 2:  Schedule of Assessments 
 
13.3. 
Appendix 3:  Medication Information Sheets  
13.4. 
Appendix 4:  Smoking Cessation Counseling Manual 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
Combining Varenicline and Naltrexone for Smoking Cessation and Drinking Reduction 
DATA ANALYSIS PLAN 
NCT02698215 
October 2018 
 
 
 


Analyses were conducted in SAS Statistical Software Version 9.4. All analyses were of the 
intention-to-treat type. Since all participants took the first dose of the study medication under 
observation during the randomization visit, all participants were included in the subsequent 
analyses. The dichotomous primary outcome for smoking cessation at the 26-week follow up 
was analyzed using a Chi-Square test comparing smoking cessation rates for the two 
medication conditions. For the purpose of these analyses, all individuals who dropped out from 
the trial were considered to have returned to smoking, per guidelines for smoking cessation 
trials. For the drinking outcomes, all of which were continuous, a series of multilevel models, via 
Proc Mixed, were conducted for each outcome separately, during the 12-week treatment period 
and for the entire 26-weeks of the trial, which is consistent with pharmacotherapy trials for 
excessive drinking. These models tested whether the two medication groups differed in alcohol 
use over the 12-week medication period and across the entire 26-weeks of the trial. All models 
for drinking outcomes controlled for baseline drinking levels.