Conditions: Obesity Smoking Cessation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 84
Healthy volunteers: yes

Brief summary:
Some individuals smoke with the perception that smoking helps control body weight. Smokers gain an average of as much as 10 pounds in the months following smoking abstinence, with heavier and more-dependent smokers gaining more weight. T The Mayo Clinic Nicotine Research Program will randomize 100 nondiabetic, overweight or obese adult smokers to active lorcaserin or placebo for 24 weeks; all of the subjects will receive open-label varenicline for 12 weeks. The purpose of this study is to assess the efficacy of a 24-week course of lorcaserin for decreasing weight gain after stopping smoking.

Detailed description:
This will be a randomized, placebo-controlled, parallel-group clinical trial. Nondiabetic, overweight and obese adult smokers will be randomized to one of three arms:

* lorcaserin for 24 weeks in combination with varenicline for 12 weeks;
* placebo for 24 weeks in combination with varenicline for 12 weeks;

We will assess the following:

* changes in weight and Weight Concern
* 7-day point-prevalence smoking abstinence weekly through week 24 and prolonged smoking abstinence at 24 and 52 weeks. Subjects will have a target quit date 8 days after starting medication.

Arms:
arm 1: Subjects will receive open label varenicline (12 weeks) plus a placebo for lorcaserin (24 weeks) arm 2: Subjects will receive open label varenicline (12 weeks) plus lorcaserin (24 weeks)

Interventions: intervention 1: lorcaserin intervention 2: Varenicline intervention 3: Placebo
Intervention descriptions: intervention 1: lorcaserin is an FDA-approved weight loss medication for overweight and obese patients intervention 2: Chantix is an FDA approved medication for smoking cessation intervention 3: Placebo for lorcaserin

Protocol document:
Prot_SAP_000.pdf: 
Addressing Post Cessation Weight Gain 
Mayo Clinic - NCT02412631 
PI: Ryan T. Hurt, MD, PhD 
MC IRB# 15-005230 
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Varenicline and lorcaserin for smoking 
cessation and weight gain prevention 
 
 
 
 
 
 
NCT02412631 
 
 
10 Jan 2018 
 


Addressing Post Cessation Weight Gain 
Mayo Clinic - NCT02412631 
PI: Ryan T. Hurt, MD, PhD 
MC IRB# 15-005230 
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General Study Information 
 
 
Study Title:    Varenicline and lorcaserin for smoking cessation and weight gain prevention 
 
Principal Investigator:      Ryan T. Hurt, MD  
 
Protocol version number and date:     10 Jan 2018 
 
Purpose 
 
Hypothesis: 
 
Weight gain associated with stopping smoking is common and is frequently identified as an important predictor 
for smoking relapse, but interventions for preventing weight gain after stopping smoking are lacking. Lorcaserin 
has potential to prevent post cessation weight gain. In this study we will: (1) investigate the impact of a novel 
pharmacologic agent on weight gain attenuation after stopping smoking; (2) evaluate a product that may have 
broad appeal among smokers to whom weight gain is a barrier to tobacco abstinence; (3) Investigate a novel 
smoking cessation combination (lorcaserin and varenicline) in a targeted population; 
 
Aims, purpose, or objectives: 
 
Cigarette smoking is the single most important preventable cause of morbidity, mortality, and excess health care 
costs in the United States. Among smokers achieving smoking abstinence, weight gain is common and may be 
an important mediator of smoking relapse. The availability of pharmacotherapy facilitating smoking abstinence 
and preventing weight gain may prompt more smokers to make quit attempts, enhance long-term smoking 
abstinence, and prevent the development of overweight or obesity among former smokers. 
 
Varenicline is a partial agonist/antagonist that binds with high affinity and selectivity at α4β2 neuronal nicotinic 
acetylcholine receptors. Varenicline is presently the most efficacious pharmacotherapy for increasing smoking 
abstinence rates, with proven superiority over bupropion SR and suggested superiority over nicotine 
replacement therapy. However, varenicline does not have a clinically meaningful effect on preventing the 
weight gain that occurs with smoking abstinence. Combining the beneficial effects of varenicline with a post 
cessation weight gain intervention might have a significant impact on weight-concerned smokers for whom 
weight gain is a significant risk factor for smoking relapse. 
 
Lorcaserin is a selective 5-HT2C receptor agonist with a 100-fold selectivity of 5-HT2C compared to the 5-HT2A 
receptor subtype. Activation of the 5-HT2C receptor subtype in the hypothalamus increases pro-
opiomelanocortin (POMC) production leading to weight loss through satiety. Three phase III studies have 
demonstrated the efficacy of lorcaserin for weight loss in overweight and obese subjects. As a result of the 
significant weight loss in these studies and the favorable side effect profile, lorcaserin was recently approved by 
the FDA for weight reduction in overweight and obese patients. No studies have evaluated the use of lorcaserin 
to reduce weight gain following stopping smoking. In addition, 5-HT2C agonists have been shown to reduce the 
stimulant, discriminative, and reinforcing effects of nicotine in animal models. No clinical studies have 
evaluated the use of 5-HT2C agonists for smoking cessation.   
 


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After stopping smoking, most of the weight gain occurs in the first 3 months. The mechanism for post cessation 
weight gain is not fully understood. Combining lorcaserin, with its effects on weight, with varenicline for 
initiating smoking abstinence may offer a unique clinical approach to the treatment of weight-concerned 
cigarette smokers. The overarching goal of this line of research is to improve smoking abstinence rates among 
cigarette smokers by intervening to reduce factors that increase the risk for smoking relapse. Our primary goal 
in this proposal is not weight loss, but rather an attenuation of the weight gain commonly observed in smokers 
who stop smoking.  
 
The primary aim and hypothesis of this study is to assess the efficacy of a 24-week course of lorcaserin for 
decreasing weight gain after stopping smoking. 
 
Hypothesis: After 24 weeks, lorcaserin will be associated with significantly less weight gain compared to 
placebo among weight-concerned adult smokers who have quit smoking with varenicline. 
 
The secondary aims and hypotheses of this study are  
1. Assess the efficacy of a 24-week course of lorcaserin for attenuating increases in BMI after stopping 
smoking. 
• 
Hypothesis: At 24 weeks, lorcaserin will be associated with a significantly lower increase in 
mean BMI than placebo among  
• 
 weight-concerned adult smokers who have quit smoking with varenicline. 
2. Assess the efficacy of the combination of 24 weeks of lorcaserin and varenicline on smoking abstinence 
rates. 
• 
Hypothesis: After 24 weeks, smoking abstinence rates will be significantly higher in subjects 
receiving lorcaserin compared to placebo when all subjects receive 12 weeks of varenicline  
 
Background:   
 
Smoking, Smoking Cessation, & Weight Concerns:  Some individuals smoke with the perception that smoking 
helps control body weight.1,2 Smokers gain an average of 5 to 10 pounds in the months following smoking 
abstinence,3,4 with heavier and more-dependent smokers gaining more weight.5,6 The mean weight gain may be 
as much as 13 pounds at one year7 and 21 pounds over 5 years.8 Actual weight gain following smoking 
abstinence has been associated with smoking relapse.9 In a large population-based study, 52% of the women 
and 32% of the men with a previous quit attempt reported that weight gain was one of the reasons for relapse to 
smoking.10 In previous research involving the prospective evaluation of a large sample of smokers, 47% of 
female smokers and 22% of male smokers were classified as having weight concerns.11  
Smoking cessation also leads to increases in visceral fat, and visceral fat is a risk factor for adverse health 
consequences. Individuals with larger amounts of visceral and organ adipose tissue have higher rates of insulin 
resistance, cardiovascular risk, and organ dysfunction.12 A large prospective cohort evaluating visceral fat area 
(VFA) measured by abdominal computed tomography observed that former smokers had higher VFA (124.0-
132.0 cm2) than current smokers (120.4 cm2) or nonsmokers (123.1 cm2).13  
 
Recent evidence has suggested that the distribution of adipose tissue is more predictive of cardiovascular risk 
than body mass index (BMI) alone.14 Central adiposity, which appears to be the best surrogate for estimating 
visceral adipose tissue, can be measured clinically as waist circumference (WC) and waist-to-hip ratio (WHR). 


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Two large case-control studies have demonstrated that WC and WHR are independent risk factors for 
cardiovascular mortality.14,15  
 
Interventions to prevent weight gain after smokers stop smoking:  Approximately 80% of smokers want to stop 
smoking and 40% attempt to stop each year. More than 90% of these self-initiated efforts are unsuccessful.4 
Intervening to affect factors such as weight gain may improve long-term smoking abstinence rates. Both 
behavioral and pharmacologic interventions have been evaluated for the prevention of weight gain after 
smoking cessation. A systematic review concluded that behavioral interventions, including general weight loss 
advice, are not effective and may reduce smoking abstinence. Studies incorporating behavioral interventions for 
both weight gain prevention and tobacco dependence suggest that participants may have difficulty complying 
with two behavioral interventions simultaneously.16 Thus, the use of a pharmacologic agent to address weight 
concerns and weight gain while the smoker focuses on the behavioral aspects of stopping smoking offers an 
attractive clinical option. Varenicline, a partial agonist/antagonist that binds with high affinity and selectivity at 
α4β2 neuronal nicotinic acetylcholine receptors, is presently the most efficacious approved pharmacotherapy 
for increasing smoking abstinence rates; however, varenicline does not have a clinically meaningful effect on 
preventing the weight gain that occurs with smoking abstinence. We have published a pilot study of the 
combination of varenicline and sibutramine17; however, sibutramine has been taken off of the market. We are 
interested in exploring the novel approach of using lorcaserin for the prevention of postcessation weight gain. 
 
Serotonin Activation and Weight Attenuation: Activation of the serotonin receptor 2 (5-HT2) has been 
associated with satiety, hypophagia, and modulation of the effects of psychostimulant addiction.18,19 Previously 
available drugs that targeted 5-HT2 (fenfluramine and dexfenfluramine) were effective in promoting weight 
loss, however these agents were nonselective. As a result of 5-HT2B receptor activation, some patients 
developed valvular heart disease and these drugs were subsequently withdrawn from the market. Lorcaserin is a 
selective 5-HT2C receptor agonist with a 100-fold selectivity of 5-HT2C compared to the 5-HT2A receptor 
subtype. Activation of the 5-HT2C receptor subtype in the hypothalamus increases pro-opiomelanocortin 
(POMC) neuron activity leading to weight loss through hypophagia and satiety. In three large phase III studies, 
there has been no valvular heart disease associated with lorcaserin.  
 
Lorcaserin and Weight Attenuation: Three phase III studies have demonstrated the efficacy of lorcaserin for 
weight loss in overweight and obese subjects. The first of these studies is the BLOOM (Behavioral 
Modification and Lorcaserin for Overweight and Obesity Management) trial which evaluated the efficacy and 
safety (including safety regarding cardiac valves) of lorcaserin used for weight loss in obese and overweight 
subjects.20 A total of 3182 subjects were randomized to receive placebo, lorcaserin 10 mg once daily, or 
lorcaserin 10 mg twice daily for 52 weeks.20 At 52 weeks, 47.5% of patients in the lorcaserin group and 20.3% 
in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 
5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001).20 Among 2472 patients 
evaluated at 52 weeks and 1127 evaluated at 104 weeks, the rate of cardiac valvulopathy was not increased with 
lorcaserin compared to placebo.20 The most frequent adverse events reported with lorcaserin were headache, 
dizziness, and nausea.20  
 
The BLOOM-DM (Behavioral Modification and Lorcaserin for Obesity and Overweight Management in 
Diabetes Mellitus) study evaluated efficacy and safety of lorcaserin for weight loss in overweight and obese 
subjects with DM2.21 A total of 604 patients were randomized to either placebo, lorcaserin 10 mg once daily, or 
lorcaserin 10 mg twice daily for 52 weeks.21 More patients lost ≥ 5% body weight with lorcaserin twice daily 


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(37.5%; P < 0.001) or lorcaserin daily (44.7%; P < 0.001) versus placebo.21 Common adverse events were 
headache, back pain, nasopharyngitis, and nausea. However, serial echocardiograms did not demonstrate 
valvular heart disease.21 Lorcaserin was associated with significant weight loss and improvement in glycemic 
control in patients with type 2 diabetes.21 As a result of the significant weight loss in these studies and the 
favorable side effect profile (including no valvular defects), lorcaserin was recently approved by the FDA and is 
currently clinically available for weight reduction in overweight and obese patients. 
 
Lorcaserin and Smoking Cessation: In addition to the effects on satiety and weight loss, serotonin activation 
appears to be involved with nicotine effects as well.22,23 Ketanserin, a 5-HT2A and 5-HT2C antagonist, 
significantly reduced nicotine self-administration in rats.23 Lorcaserin has been shown to reduce nicotine self-
administration in two animal studies. The first used self-administered subcutaneous doses of nicotine (0.03 
mg/kg per infusion) with fixed doses of lorcaserin (0.3125-20 mg/kg) in rats for 2 weeks.23 Nicotine self-
administration was reduced in all doses of lorcaserin compared to placebo. The second study used self-
administered subcutaneous doses of nicotine, and all doses of lorcaserin reduced self-administration.22 
Furthermore, lorcaserin produced a dose-dependent reduction of nicotine induced hyperactivity.22 These studies 
support the hypothesis that lorcaserin could potentially aid in smoking cessation in addition to attenuate 
postcessation weight gain. No clinical study has been published evaluating the use of lorcaserin to attenuate 
weight gain in smokers who stop smoking. 
 
Mechanism of Postcessation Weight Gain: Despite the convincing evidence for the association between 
smoking cessation and weight gain, the molecular mechanisms involved are not well understood. Energy 
homeostasis is a complex interaction between adipose tissue and the hypothalamus. The role of leptin and 
neuropeptide Y (NPY) in obesity has been well established.24,25 NPY is released by the hypothalamus and gut 
and is one of the most potent orexigenic (appetite stimulant) neuropeptides known.24 Leptin is released by 
adipose tissue and counteracts the effects of NPY and induces appetite suppression.26,27 Increasing adiposity can 
lead to increased leptin resistance with increased circulating levels of leptin.26,27 A recent study has evaluated 
the role of NPY and leptin in postcessation weight gain.28 Plasma levels of NPY and leptin in 35 nonsmokers 
and 31 cigarette smokers before and three months after smoking cessation were evaluated.28 Compared to 
nonsmokers, smokers were leaner and had reduced NPY and leptin levels. Smoking cessation resulted in a 
significant weight gain and increased WC which was associated with increased leptin and NPY. 
 
Subject Information – charts, records, images, or specimens are considered ‘subjects’ 
 
Target accrual: 100 
 
Subject population:  A total of 100 daily smokers (≥10 cigarettes/day for ≥6 months)  
 
Inclusion Criteria:  
1. ≥18 years and ≤65 years of age;  
2. smoked ≥10 cigarettes/day for the past 6 months;  
3. BMI of 27–39.9 kg/m2;  
4. motivated to stop smoking;  
5. weight concerned as shown with the Weight Concern Scale;  
6. able to participate fully in all aspects of the study;  
7. understand and signed the study informed consent. 


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8. Subject is in good health as determined by the clinical investigators. 
 
Exclusion Criteria:   
1. current nonspecific suicidal thoughts or a lifetime history of a suicidal attempt (defined by the 
Columbia-Suicide Severity Rating Scale [C-SSRS] as a “potentially self-injurious act committed with at 
least some wish to die, as a result of act.”);  
2. current moderate or severe depression as assessed by a score of ≥16 on the Center for Epidemiologic 
Studies-Depression (CES-D);  
3. a lifetime history of psychosis, bipolar disorder or schizophrenia;  
4. use of anti-psychotic medication within the past 30 days;  
5. use of weight-loss medications within the past 30 days or current participation in a program specifically 
designed to help with weight loss;  
6. weight fluctuations of 20 pounds or more in the past 6 months (self-report);  
7. use of any treatments for tobacco dependence within the past 30 days;  
8. use of an investigational drug within the past 30 days;  
9. recent history (past 3 months) of abuse of or dependence on a substance other than tobacco.  Including: 
heavy alcohol consumption (If male, drinking > 4 alcoholic beverages per day for past month and if 
female, drinking > 3 alcoholic beverages per day for past month); use of cocaine, heroin, club drugs 
(i.e., MDMA/“ecstasy”), methamphetamine, or hallucinogens (e.g., LSD) at any time during the past 3 
months; and  use of marijuana on a weekly basis for the past 3 months 
10. current use of triptans, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), 
selective serotoninnorepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic 
antidepressants (TCAs), bupropion, lithium, tramadol, tryptophan, and St. John’s Wort, or any other 
medication known to involve the serotonergic neurotransmitter system (see human subjects section);  
11. uncontrolled hypertension (systolic >160 mm Hg and/or diastolic >100 mm Hg) documented on 2 
separate occasions;  
12. current use of medications known to interact with varenicline or lorcaserin.  These can include 
benzodiazepines, narcotics, anti-epileptics;  
13. another household member or relative participating in the study;  
14.  insulin dependent diabetic or unstable type 2 diabetic on oral diabetic medications.  
15. a known allergy to varenicline or lorcaserin.  
16. Women who are pregnant or lactating, or who are of childbearing potential and are likely to become 
pregnant during the medication phase but are not willing to use a reliable form of contraception, will 
also be excluded. Reliable forms of contraception include oral contraception, diaphragm or condom 
(with spermicide), injections, intrauterine device, surgical sterilization, and abstinence. 
17. Has an unstable medical condition as determined by the physician investigator 
18. Subject describes having a medical history of: a) unstable angina; b) myocardial infarction within the 
past 3 months; c) coronary angioplasty or d) an untreated cardiac dysrhythmia. 
19. Subject currently has cancer [excluding non-melanoma skin cancer] not in remission 
20. Known history of seizures 
 
Will a Certificate of Confidentiality (COC) be obtained from NIH?   
 Yes  
  No    
 
Study Design  
Methods:  


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This will be a randomized, placebo-controlled, parallel-group clinical trial.   Overweight and obese adult 
smokers will be randomized to one of two arms:  
• 
lorcaserin for 24 weeks in combination with varenicline for 12 weeks;  
• 
placebo for 24 weeks in combination with varenicline for 12 weeks;  
 
We will assess the following:  
• 
changes in weight, WC, and BMI  
• 
7-day point-prevalence smoking abstinence weekly through week 24 and prolonged smoking 
abstinence at 24 and 52 weeks. Subjects will have a target quit date 8 days after starting medication. 
 
Study Medications 
• 
Varenicline: Varenicline is an oral medication with a recommended dosage of 0.5 mg once daily for 
3 days, increasing to 0.5 mg twice daily for days 4 to 7, and then to the maintenance dose of 1 mg 
twice daily for the remaining 11 weeks of treatment. The target quit date (TQD) will be one day after 
the one-week dose-escalation treatment (day 8 of therapy). Varenicline will be continued for a total 
of 12 weeks.  
• 
Lorcaserin: Lorcaserin is an oral medication with a recommended dosage of 10 mg twice daily. 
Subjects will be randomized to receive either (1) active lorcaserin for 24 weeks simultaneously with 
active varenicline, (2) placebo lorcaserin for 24 weeks simultaneously with active varenicline. 
Lorcaserin will be taken in a dose of 10 mg twice daily. The placebo for lorcaserin and will be 
encapsulated with the assistance of the Mayo Clinic inpatient pharmacy, which will also help with 
the distribution of study medication and instructions for its use.   
 
Subject Retention: Participants will be remunerated up to $145, prorated to the number of completed visits.   
 
Statistical Information 
 
Statistical Considerations 
 
Statistical Design/Randomization:  
 
A randomization program will be generated using SASDMS to randomize patients using a ratio of 1:1 
assignment to Placebo + varenicline or Lorcaserin + varenicline.  The randomization will be stratified by sex 
(Male/Female) and BMI (27-34.9 and 35-39.9).  
 
All study medication will be labeled and dispensed according to subject ID by the Mayo Clinic Pharmacy. 
 
Definitions: 
• Height, Body Weight, and Waist Circumference: The primary outcome will be weight gain at 24 weeks, 
and a secondary outcome will be WC at 24 weeks. Height will be measured in stocking feet using a 
vertical stadiometer. Body weight will be measured with a digital scale that will be calibrated on a 
regular basis using certified weights. Participants will be measured with their shoes and heavy outer 
garments removed and pockets emptied. BMI will be calculated (as kg/m2) from measured weight and 
height. The WC measurement will be standardized in the following way: While the subject is standing 


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upright, a measuring tape will be held in the horizontal plane around the bare abdomen at the iliac crest, 
and measurements will be taken at the end of a normal expiration with the tape snug and not 
compressing the skin. 
• Smoking Abstinence definitions: Smoking abstinence definitions are based upon published 
recommendations:49 
o Point-prevalence smoking abstinence will be adjudicated if both of the following criteria are 
met: (1) Self-reported smoking abstinence for the last 7 days defined as a negative response to 
the question, “Have you used any type of tobacco, even a puff, in the past 7 days;” and (2) 
Expired air CO <8 ppm. 
o Prolonged smoking abstinence will be adjudicated if the following criteria are met: 1) Self-
reported smoking abstinence since 2 weeks after target quit date (TQD). Negative response to the 
question, “Have you used any type of tobacco, even a puff, for 7 consecutive days or at least 
once each week on two consecutive weeks since xx/xx/xxxx?”, where xx/xx/xxxx corresponds to 
the date 2 weeks after the TQD; 2) Biochemically confirmed smoking abstinence at the visit for 
which prolonged smoking abstinence is being obtained. 
 
Power Statement:   
The primary aim of the current study is to obtain preliminary evidence of the efficacy of a 24-week course of 
lorcaserin (10 mg twice a day) in attenuating weight gain in weight-concerned adult smokers who use 
varenicline to stop smoking. With this aim in mind, we have designed a randomized phase II screening trial to 
decide whether a larger study of this experimental regimen is warranted and to provide preliminary data for 
designing a larger phase III trial to confirm efficacy.50  
 
For this study, the primary endpoint will be weight change from baseline to week 24 among subjects receiving 
active varenicline who meet criteria for prolonged smoking abstinence at week 24. In a trial evaluating the 
potential efficacy of maintenance therapy with varenicline, the point-prevalence abstinence rate after 12 weeks 
of open-label varenicline treatment was 64.1%,30 and in our pilot study of sibutramine and varenicline the 
prolonged smoking abstinence rate at week 12 was 60%.17 In order to be conservative, for the present study we 
assume that 30% of the subjects enrolled in the current trial who receive active varenicline will meet criteria for 
prolonged smoking abstinence at 24 weeks. In two large randomized trials assessing the efficacy of 12 weeks of 
varenicline for initiating smoking abstinence, the mean ± SD weight change from baseline at week 12 among 
subjects assigned to varenicline who were abstinent from smoking for weeks 9-12 was 2.89 ± 2.95 kg and 
2.37 ± 2.95 kg.31,51 From these studies, we assume that the standard deviation of weight change from baseline at 
24 weeks among subjects who meet criteria for prolonged smoking abstinence will be 3.0 kg. We believe that 
an intervention that reduces weight gain by 2.0 kg or more would warrant further investigation. Using these 
assumptions, we have determined that an effective sample size of n = 15 subjects per group who meet criteria 
for prolonged smoking abstinence will provide statistical power (one-tailed, alpha = 0.20) of 82% to provide 
preliminary evidence of the efficacy of lorcaserin in attenuating weight gain for smokers who stop smoking 
using varenicline.  Under the assumption that the prolonged smoking abstinence rate will be 30%, we propose a 
sample-size of N=50 per group. 
 
Data Analysis Plan:  
We will use descriptive statistics to summarize baseline characteristics (e.g. age, ethnicity, education, and 
results of the WEL Questionnaire, WCS, Control of Eating Questionnaire, and CES -D) and tobacco use history 
(e.g., cigarettes per day, FTND). Summaries will be generated for the entire sample, as well as according to 


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treatment group both overall and for those who meet the criteria for prolonged smoking abstinence at 24 weeks. 
For the primary endpoint of weight change at week 24 among subjects receiving active varenicline who meet 
the criteria for prolonged smoking abstinence, values will be compared between treatment groups using a one-
tailed test with a P value ≤ 0.20 used as evidence to suggest that a larger phase III study should be pursued.50 
For consistency, one-tailed P values will also be reported for the secondary endpoints of WC and blood 
pressure. For the prolonged abstinence endpoints we will also use one-tailed, alpha=0.20 level tests as evidence 
to suggest further studies are warranted. For all other analyses, two-tailed P values will be reported. In all cases, 
treatment effects will be presented using point estimates and 90% confidence intervals. 
 
Endpoints 
   Primary: Lorcaserin will be associated with significantly less weight gain than placebo in weight-concerned 
adult smokers who are treated simultaneously with varenicline for 12 weeks and are meet criteria for prolonged 
abstinence at the end of the lorcaserin medication phase (24 weeks). 
• Secondary: Lorcaserin will be associated with significantly decreased WC and BMI compared to 
placebo in weight-concerned adult smokers who meet criteria for prolonged abstinence at the end of the 
medication phase (24 weeks). Weight change from baseline to 24 weeks among subjects who meet 
criteria for prolonged smoking abstinence will be compared between groups using the two-sample t-test. 
For this analysis, a P value ≤ 0.20 will be used as evidence to suggest that a larger phase III study should 
be pursued.50 Similar analyses will be performed for the secondary endpoints of WC and BMI. Subjects 
who discontinue study participation will not meet criteria for prolonged smoking abstinence. For this 
reason, there should not be any missing data for the primary analysis. We will also perform secondary 
analyses that include all randomized subjects. For these analyses, we will use multiple imputation to 
impute values for subjects who discontinue study participation prior to 24 weeks. In all cases, we will 
assess distributional assumptions and use transformations or non-parametric analyses as appropriate.  
 
 
REFERENCES 
 
1. 
Klesges R, Zbikowski S, Lando H, Haddock C, Talcott G, Robinson L. The relationship between 
smoking and body weight in a population of young military personnel. Health Psychol. 1998;17(5):454-
458. 
2. 
Cavallo DA, Duhig AM, McKee S, Krishnan-Sarin S. Gender and weight concerns in adolescent 
smokers. Addict. Behav. Nov 2006;31(11):2140-2146. 
3. 
Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence:  2008 Update. Clinical 
Practice Guideline 2008; www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf. Accessed 
October 12, 2011. 
4. 
Flegal KM, Troiano RP, Pamuk ER, Kuczmarski RJ, Campbell SM. The influence of smoking cessation 
on the prevalence of overweight in the United States. N. Engl. J. Med. Nov 2 1995;333(18):1165-1170. 
5. 
Williamson DF, Madans J, Anda RF, Kleinman JC, Giovino GA, Byers T. Smoking cessation and 
severity of weight gain in a national cohort. New Engl J Med. 1991;324(11):739-745. 
6. 
Hudmon KS, Gritz ER, Clayton S, Nisenbaum R. Eating orientation, postcessation weight gain, and 
continued abstinence among female smokers receiving an unsolicited smoking cessation intervention. 
Health Psychol. Jan 1999;18(1):29-36. 


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7. 
Klesges RC, Winders SE, Meyers AW, et al. How much weight gain occurs following smoking 
cessation? A comparison of weight gain using both continuous and point prevalence abstinence. J. 
Consult. Clin. Psychol. Apr 1997;65(2):286-291. 
8. 
Eisenberg D, Quinn BC. Estimating the effect of smoking cessation on weight gain: an instrumental 
variable approach. Health Serv. Res. Dec 2006;41(6):2255-2266. 
9. 
Borrelli B, Mermelstein R. The role of weight concern and self-efficacy in smoking cessation and 
weight gain among smokers in a clinic-based cessation program. Addict. Behav. 1998;23(5):609-622. 
10. 
Pisinger C, Jorgensen T. Waist circumference and weight following smoking cessation in a general 
population: the Inter99 study. Prev. Med. Apr 2007;44(4):290-295. 
11. 
Meyers A, Klesges RC, Winders S, Ward K, Peterson B, Eck L. Are weight concerns predictive of 
smoking cessation? A prospective analysis. J. Consult. Clin. Psychol. 1997;65(3):448-452. 
12. 
Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. Dec 14 
2006;444(7121):881-887. 
13. 
Matsushita Y, Nakagawa T, Yamamoto S, Takahashi Y, Noda M, Mizoue T. Associations of smoking 
cessation with visceral fat area and prevalence of metabolic syndrome in men: the Hitachi health study. 
Obesity. Mar;19(3):647-651. 
14. 
Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 
participants from 52 countries: a case-control study. Lancet. Nov 5 2005;366(9497):1640-1649. 
15. 
Dhaliwal SS, Welborn TA. Central obesity and multivariable cardiovascular risk as assessed by the 
Framingham prediction scores. Am J Cardiol. May 15 2009;103(10):1403-1407. 
16. 
Pirie P, McBride C, Hellerstedt W, et al. Smoking cessation in women concerned about weight. Am. J. 
Public Health. 1992;82:1238-1243. 
17. 
Sood A, Ebbert JO, Clark MM, Croghan IT, Schroeder DR, Hays JT. Sibutramine for weight gain 
attenuation during smoking cessation with varenicline: a pilot study. Nicotine Tob. Res. Dec 
2009;11(12):1479-1484. 
18. 
Katsidoni V, Apazoglou K, Panagis G. Role of serotonin 5-HT2A and 5-HT2C receptors on brain 
stimulation reward and the reward-facilitating effect of cocaine. Psychopharmacology. Feb 2011;213(2-
3):337-354. 
19. 
Bubar MJ, Cunningham KA. Serotonin 5-HT2A and 5-HT2C receptors as potential targets for 
modulation of psychostimulant use and dependence. Curr Top Med Chem. 2006;6(18):1971-1985. 
20. 
Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for 
weight management. New England Journal of Medicine. Jul 15 2010;363(3):245-256. 
21. 
O'Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for 
weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). Jul 
2012;20(7):1426-1436. 
22. 
Higgins GA, Silenieks LB, Rossmann A, et al. The 5-HT2C receptor agonist lorcaserin reduces nicotine 
self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse 
control. Neuropsychopharmacology. Apr 2012;37(5):1177-1191. 
23. 
Levin ED, Johnson JE, Slade S, et al. Lorcaserin, a 5-HT2C agonist, decreases nicotine self-
administration in female rats. J. Pharmacol. Exp. Ther. Sep 2011;338(3):890-896. 
24. 
Beck B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philosophical 
Transactions of the Royal Society of London. Series B: Biological Sciences. Jul 29 
2006;361(1471):1159-1185. 
25. 
Myers MG, Jr., Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause 
from effect. Trends Endocrinol Metab. Nov 2010;21(11):643-651. 


Addressing Post Cessation Weight Gain 
Mayo Clinic - NCT02412631 
PI: Ryan T. Hurt, MD, PhD 
MC IRB# 15-005230 
Page 11 of 12 
Created on 3/30/2021 11:23 AM 
 
26. 
Cota D, Barrera JG, Seeley RJ. Leptin in energy balance and reward: two faces of the same coin? 
Neuron. Sep 21 2006;51(6):678-680. 
27. 
Korda M, Kubant R, Patton S, Malinski T. Leptin-induced endothelial dysfunction in obesity. Am J 
Physiol Heart Circ Physiol. Oct 2008;295(4):H1514-1521. 
28. 
Hussain T, Al-Daghri NM, Al-Attas OS, Draz HM, Abd Al-Rahman SH, Yakout SM. Plasma 
neuropeptide Y levels relate cigarette smoking and smoking cessation to body weight regulation. Regul. 
Pept. Jun 10 2012;176(1-3):22-27. 
29. 
Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in 
obese and overweight adults: the BLOSSOM trial. The Journal of clinical endocrinology and 
metabolism. Oct 2011;96(10):3067-3077. 
30. 
Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy 
with varenicline on smoking cessation: a randomized controlled trial. JAMA. Jul 5 2006;296(1):64-71. 
31. 
Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine 
receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized 
controlled trial. JAMA. Jul 5 2006;296(1):56-63. 
32. 
Williams KE, Reeves KR, Billing CB, Jr., Pennington AM, Gong J. A double-blind study evaluating the 
long-term safety of varenicline for smoking cessation. Curr. Med. Res. Opin. Apr 2007;23(4):793-801. 
33. 
Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting cigarettes: 
meta-analysis. BMJ. 2012;345:e4439. 
34. 
Mermelstein RM, Karnatz TK, Reichmann S. Smoking In: Wilson PH, ed. Principles and practice of 
relapse prevention. New York: Guildford Press; 1992:43-68. 
35. 
Hall SM, Tunstall CD, Vila KL, Duffy J. Weight gain prevention and smoking cessation: cautionary 
findings. Am. J. Public Health. 1992;82(6):799-803. 
36. 
Cheskin LJ, Hess JM, Henningfield J, Gorelick DA. Calorie restriction increases cigarette use in adult 
smokers. Psychopharmacology (Berl). May 2005;179(2):430-436. 
37. 
Woods NF, Lentz M, Mitchell E, Oakley LD. Depressed mood and self-esteem in young Asian, black, 
and white women in America. Health Care Women Int. May-Jun 1994;15(3):243-262. 
38. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. Br. J. Addict. Sep 1991;86(9):1119-
1127. 
39. 
Clark M, Abrams D, Niaura R, Eaton C, Rossi J. Self-efficacy in weight management. J. Consult. Clin. 
Psychol. 1991;59(5):739-744. 
40. 
Pinto B, Clark M, Szymanski L, Cruess D, Pera V. Changes in self-efficacy and decisional balance for 
exercise among obese women in a weight management program. Obes. Res. 1999;7:288-292. 
41. 
Greenway FL, Bray GA. Combination drugs for treating obesity. Curr Diab Rep. Apr 2010;10(2):108-
115. 
42. 
Hyland M, Sodergren S. Development of a new type of global quality of life scale, and comparison of 
performance and preference for 12 global scales. Qual. Life Res. 1996;5(5):469-480. 
43. 
Dyrbye LN, Thomas MR, Huschka MM, et al. A multicenter study of burnout, depression, and quality 
of life in minority and nonminority US medical students. Mayo Clinic proceedings. Mayo Clinic. Nov 
2006;81(11):1435-1442. 
44. 
Locke DE, Decker PA, Sloan JA, et al. Validation of single-item linear analog scale assessment of 
quality of life in neuro-oncology patients. J. Pain Symptom Manage. Dec 2007;34(6):628-638. 
45. 
Cash T. The Multidimensional Body-Self Relations Questionnaire User's Manual. Norfolk, VA1994. 


Addressing Post Cessation Weight Gain 
Mayo Clinic - NCT02412631 
PI: Ryan T. Hurt, MD, PhD 
MC IRB# 15-005230 
Page 12 of 12 
Created on 3/30/2021 11:23 AM 
 
46. 
Cash T. User's manuals for the Multidimensional Body-Self Relations Questionnaire, the Situational 
Inventory of Body-Image Dysphoria, and the Appearance Schemas Inventory: Available from the author 
at www.body-images.com; 2000. 
47. 
Clark MM, Croghan IT, Reading S, et al. The relationship of body image dissatisfaction to cigarette 
smoking in college students. Body Image. Sep 2005;2(3):263-270. 
48. 
Avalos L, Tylka TL, Wood-Barcalow N. The Body Appreciation Scale: development and psychometric 
evaluation. Body Image. Sep 2005;2(3):285-297. 
49. 
Hughes JR, Keely JP, Niaura RS, Ossip-Klein DJ, Richmond RL, Swan GE. Measures of abstinence in 
clinical trials: issues and recommendations. Nicotine Tob Res. Feb 2003;5(1):13-25. 
50. 
Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized 
phase II trials and a proposal for phase II screening trials. J Clin Oncol. Oct 1 2005;23(28):7199-7206. 
51. 
Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor 
partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized 
controlled trial. JAMA. Jul 5 2006;296(1):47-55.