A Randomized Controlled Trial of Lifestyle Modification and Lorcaserin for Weight Loss Maintenance
Phase: NA
Conditions: Obesity
Sponsor: University of Pennsylvania

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Version 8.0 January 25, 2016 
University of Pennsylvania 
Center for Weight and Eating Disorders 
3535 Market Street Suite 3108 
Philadelphia, PA 19104 
Phone: 215-898-7314 
Fax: 215-898- 2878 
 
 
Title: A Randomized Controlled Trial of Lifestyle Modification and Lorcaserin for Weight 
Loss Maintenance 
 
 
Principal Investigator:  
Thomas A. Wadden, Ph.D. 
 
Co- Investigators: 
  
Robert I. Berkowitz, M.D. 
                               
  
Nasreen Alfaris, M.D., M.P.H. 
 
 
 
 
Naji Alamuddin, M.D. 
 
 
 
 
Ariana Chao, Ph.D. 
 
 
 
 
Rebecca Pearl, Ph.D. 
 
 
 
 
Jena Shaw, Ph.D. 
                                
Study Site:  
 
 
Center for Weight and Eating Disorders 
                      
 
University of Pennsylvania 
 
 
1. STUDY OBJECTIVE 
 
To evaluate, in a 52-week randomized, double-blind, placebo-controlled trial, the efficacy of 
lorcaserin (10 mg BID) in maintaining a loss of 5% or more of initial weight, achieved during a 
prior 14-week group lifestyle modification program. 
 
2. BACKGROUND 
 
2.1 The Problem of Obesity 
 
Obesity, defined by a BMI ≥ 30 kg/m², is the most common nutritional disease in the United 
States, affecting about 36% of adults age 20 years and over. An additional 33% of American 
adults are overweight, as judged by a BMI of 25.0-29.9 kg/m². Obesity is associated with a 
number of co-morbidities including type 2 diabetes (70% of people with type 2 diabetes are 
obese) and cardiovascular disease. Losing as little as 5% of initial weight improves co-morbid 
conditions including insulin resistance, dyslipidemia, and hypertension.  
 
A program of diet, physical activity and behavioral therapy is the first line treatment for obesity. 
This approach produces significant weight loss (≥5%) but is often followed by weight gain. 
Patients regain about 35% of their initial weight loss in the first year and 50% or more have 

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returned to their baseline weight by 5 yr. It is therefore, highly desirable to identify effective 
interventions, which would improve long-term maintenance of prior weight loss. 
 
 
 
 
2.2 Benefits of Weight loss 
 
A 5–10% reduction in body weight in obese individuals improves several risk factors for 
cardiovascular disease (CVD) including blood pressure, triglyceride levels, low-density-
lipoprotein cholesterol, blood glucose, and sleep apnea.1-3 The Diabetes Prevention Program 
(DPP) revealed that a 7% reduction in initial weight, combined with 150 minutes of activity, 
reduced the risk of developing type 2 diabetes by 58%, compared with placebo, in at-risk 
overweight/obese individuals at an average of 2.8 years follow-up.4  Losses >10% are associated 
with greater improvements in CVD risk factors5 and are more consistent with obese individuals’ 
desired weight loss goals. 6 
 
2.3 Current Status of Lifestyle Modification for Obesity  
 
Lifestyle modification is the cornerstone of treatment for most obese individuals, as 
recommended by the NHLBI’s Clinical Guidelines on the Identification, Evaluation, and 
Treatment of Overweight and Obesity in Adults.7 In trials conducted in academic medical 
centers, persons treated by a 1200-1500 kcal/d diet, combined with regular exercise and a 
comprehensive program of group or individual lifestyle modification, lose approximately 7-10% 
of initial weight in 20-26 weeks.4,7,8 Lifestyle modification has been incorporated in popular 
commercial programs such as Weight Watchers,9,10 which was found in a randomized trial to 
induce a loss of 5.3% of initial weight in the first 26 weeks (and 3.3% at year 2).10 Diet and 
exercise interventions are increasingly delivered by Internet,11,12 the most effective program which 
induced a loss of 5.5% of initial weight in 6 months.12 The reduced efficacy of lifestyle modification in 
these two cases, as compared with when delivered at academic medical centers, is probably attributable 
to the use of large group sessions (50 or more people) which limit individual attention (i.e., Weight 
Watchers) and to the lack of frequent, personalized feedback from a trained interventionist (i.e., Internet 
programs). The use of telephone-delivered lifestyle counseling produces weight losses that are roughly 
equal to those achieved in face-to-face meetings,13-15 suggesting the promise of the former approach.   
 
 
2.4 Improving the Non-Surgical Treatment of Obesity 
 
2.4.1 Increasing initial weight losses  
 
Investigators currently are examining methods to increase initial weight losses and, thus, achieve 
greater improvements in CVD risk factors. The use of portion-controlled servings of 
conventional foods,16 as well as liquid meal replacements,3,17 is effective in increasing initial 
weight losses by approximately 3 to 5 percentage points, as compared with the prescription of a 
self-selected diet of conventional foods with the same calorie goal. Portion-controlled servings, 
by providing foods of pre-determined quantity and energy content, reduce obese individuals’ 

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tendency to underestimate their calorie intake, which has been found to be as great as 40% when 
a self-selected diet of conventional foods is consumed.18,19 The use of liquid meal replacements 
and snack bars contributed to the 8.6% reduction in initial weight achieved in the first year of the 
Look AHEAD study.20  
 
The addition of pharmacotherapy to lifestyle modification also increases initial weight loss, by 
approximately 3 to 7 percentage points compared with lifestyle modification alone. This additive benefit 
is observed whether participants receive a modest program of lifestyle modification (e.g., one or two 
visits with an interventionist)21 or a comprehensive program (i.e., weekly group meetings).22,23 Current 
medications approved by FDA for chronic weight management include orlistat (a gastric and 
pancreatic lipase inhibitor),24,25 lorcaserin (a selective serotonin agonist),26 and the combination 
of phentermine and topiramate (a serotonin and dopamine reuptake inhibitor, combined with a 
medication for epilepsy/seizure).21,27  
 
2.4.2 Improving the maintenance of lost weight 
 
Weight regain remains the Achilles’ heel of behavioral treatment.8,18 Obese adults, on average, 
regain one-third of their weight loss in the year following treatment, with increasing regain over 
time.8 Two approaches facilitate the maintenance of lost weight. Lifestyle counseling, on a 
twice-monthly or monthly basis, improves weight maintenance for up to 2.5 years compared 
with no further treatment.28,29 Pharmacological treatment offers another option. Several studies 
have revealed significantly better weight-loss maintenance at 1 or more years in individuals who 
were randomly assigned, following initial weight loss, to receive weight-loss medication versus 
placebo.24,26,30-32 FDA-approved weight loss medications are an option for individuals with a 
BMI ≥ 30 kg/m² or persons with a BMI ≥ 27 kg/m² with a weight-related co-morbidity (e.g., type 
2 diabetes, hypertension, etc.). 
 
2.4.3 Lorcaserin 
 
Lorcaserin (BelviqTM) is a selective serotonin 2C receptor agonist that improves the management 
of obesity. A randomized, controlled trial compared two doses of lorcaserin (10 mg BID vs 10 
mg QD) with placebo, all of which were combined with moderate intensity lifestyle 
counseling.33 Significantly more participants in the lorcaserin BID and QD groups lost >5% of 
initial weight than with placebo (47.2%, 40.2, and 25.0%, respectively). A second trial that 
compared locaserin (10 mg BID) and placebo (both with lifestyle counseling) observed 1-year 
mean (SEM) weight losses of 5.8+0.2% and 2.2+0.1% of initial weight, respectively.26 
Significantly more participants treated by lorcaserin than placebo lost 5% or more of  initial 
weight (47.5% vs 20.3%), as well as 10% or more (22.6% vs 7.7%).3  
 
Lorcaserin clearly is effective in inducing weight loss. However, it could prove to be even more 
beneficial in facilitating the maintenance of lost weight, by far the greater challenge in weight 
management. Studies of both sibutramine (10-15 mg/d)30 and liraglutide (3.0 mg/d)34 showed 
that following the loss of approximately 6%-7% of initial weight, achieved with lifestyle 
modification (i.e., diet run-in), the subsequent addition of medication increased weight loss by an 
additional 5%-6% over 12 months. With both medications, long-term weight loss was superior in 
patients who received medication (plus lifestyle intervention) than placebo (with lifestyle 

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intervention). Sibutramine is no longer available for the treatment of obesity (because of its 
association with cardiovascular disease) and liraglutide 3.0 mg is not approved for the 
management of obesity at this time. Orlistat, while superior to placebo, was not effective in 
facilitating the maintenance of lost weight achieved during a diet run-in period.32 Neither the 
efficacy of lorcaserin nor the phentermine-topirimate combination has been tested for facilitating 
the maintenance of lost weight, achieved with a prior group lifestyle modification program. In a 
previously discussed study, 26 participants who received lorcaserin and lost 5% or more of initial 
weight at 1 year, were more likely to maintain the 5% loss at year 2 if they had been re-
randomized to lorcaserin rather than to placebo at the end of year 1. Sixty-eight percent of 
participants who remained on lorcaserin for the second year maintained the 5% loss, compared 
with 50% of those who were randomized after 1 year to placebo. 26 The goal of the present study 
is to maintain larger long-term weight losses by inducing larger initial losses with the group 
lifestyle modification program. 
 
3. SPECIFIC AIMS 
 
3.1 Primary Objective 
 
The primary objective is to assess the efficacy of lorcaserin (with lifestyle intervention), 
compared with placebo (with lifestyle intervention) in facilitating the maintenance of prior 
weight loss achieved during a 14-week group lifestyle modification program. The efficacy of 
lorcaserin will be measured by change in weight (kg) from randomization to week 52. The co-
primary outcome will compare the percentage of participants assigned to lorcaserin vs placebo 
who maintained the loss of 5% or more of initial weight, achieved during the 14-week dietary 
run-in period. 
 
3.2 Hypotheses 
 
We hypothesize that at 52 weeks post randomization the group assigned to lorcaserin will 
achieve significantly better maintenance of the prior 5% weight loss than will the placebo-treated 
group. 
 
3.3 Primary End Point 
 
The primary end point is the maintenance of weight loss (previously achieved during the 14-
week lifestyle modification program), as defined by change in weight (kg) from randomization to 
week 52. The co-primary end-point is the percentage of participants in each group that maintain 
the full 5% weight loss, achieved in the 14-week prior group lifestyle modification program. 
 
3.4 Secondary Endpoints 
 
 Secondary endpoints include percentage change in body weight from randomization to week 52, 
as well the portion of participants in the two groups who achieve an additional loss >5% of body 
weight, as measured from randomization. The two groups also will be compared on changes 
(from randomization to week 52) in cardiometabolic risk factors (including waist circumference, 
systolic and diastolic blood pressure, triglyceride values, LDL and HDL cholesterol, glucose, 

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insulin, and high sensitivity C-reactive protein), quality of life (as measured by the Short Form 
Health Survey [SF-36] and the Impact of Weight on Quality of Life-Lite [IWQOL]),  appetite 
control (as measured by the Eating Inventory, visual analogue scales, the Eating Disorder 
Examination-Questionnaire,and the Yale Food Addiction Scale), frequency with which certain 
foods are eaten (as measured by the Block Food Frequency Questionnaire, and physical activity 
will be assessed by the Paffenbarger Physical Activity Survey. 
The proportion of participants who maintain losses >10% and >15% of initial weight, as 
measured from the start of the 14-week group lifestyle modification program, also will be 
compared.  
 
4. STUDY DESIGN 
 
4.1 General Design 
 
This is a 52 week, double blind, placebo controlled, parallel group design trial that will enroll 
overweight/obese participants who achieved a >5% weight loss in a prior 14-week group 
lifestyle modification program. The total duration of the study will be 70 weeks (which includes 
a final medical visit at 56 weeks post-randomization to assess participants’ health 4 weeks after 
the trial and study medications have been stopped). 
 
A total of 182 obese men and women (body mass index [BMI] >33 and <55 kg/m2or BMI>30 
kg/m2 with an obesity-related comorbidity) will be enrolled in a 14-week group lifestyle 
modification program  (offered at the University of Pennsylvania’s Center for Weight and Eating 
Disorders), of whom ≥136 (75%) are expected to lose >5% of initial weight and will be eligible 
for randomization to lorcaserin (with lifestyle intervention; N=68) or placebo (with lifestyle 
intervention; N=68).  (Note: A portion of the lifestyle intervention program will be provided 
remotely by conference call)  
 
Other Therapy: 
 
Participants will be expected to use medications (prescribed by their primary care providers)  to 
control traditional cardiometabolic risk factors (e.g., hypertension, , hypercholesterolemia, etc) 
and other co-morbid conditions, with the exception of medications listed below under 
“exclusions.” In all cases, the subjects’ primary care provider (PCP) will be asked at the study’s 
outset to keep medication does constant throughout the study, whenever possible. Participants 
will be expected to have been on their medication regimen (including the dose) for 3 months 
prior to entering the dietary group lifestyle modification program. 
 
 
5. SUBJECT SELECTION 
 
5.1 Subject Recruitment 
 
Participants will be recruited from advertisements in local media outlets (newspapers, radio), as well 
as flyers posted at the University.  We also will advertise the study to health care providers who work 
in Penn’s Clinical Care Associate practices, with whom we have collaborated previously.35  

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5.2 Inclusion/Exclusion Criteria 
 
 Key Inclusion Criteria to enter the 14-week group-lifestyle modification program: 
 
 
1.  BMI  ≥33 kg/m² and ≤55 kg/m² (or  ≥30 kg/m² with an obesity-related comorbidity) 
2. Age ≥ 21 years and ≤ 65 
3. Eligible female patients will be: 
 non-pregnant, evidenced by a negative urine dipstick pregnancy test 
 non-lactating 
 surgically sterile or postmenopausal, or they will agree to continue to use an 
accepted method of birth control during the study  
Acceptable methods of birth control are: hormonal contraceptives; double barrier 
method (condom with spermicide or diaphragm with spermicide); intrauterine 
device; surgical sterility; abstinence; and/or postmenopausal status (defined as at 
least 2 years without menses).  
 
4.    Participants must: 
 have a PCP who is responsible for providing routine care 
 have reliable telephone service  with which to participate in conference calls 
 understand and be willing to comply with all study-related procedures and agree 
to participate in the study by giving written informed consent 
 
  
 
 Key Exclusion Criteria: 
 
1. Pregnant or nursing (or plans to become pregnant in the next 18 months) 
2. Current major depressive episode, active suicidal ideation, or history of suicide attempts 
3. Use in the past 14 days of monoamine oxidase inhibitors, SSRI, SNRI, tricyclics, lithium, 
triptans, antipsychotics, cabergoline, linezolid, tramadol, dextromethorphan, tryptophan, 
bupropion, St. John’s Wort, or medicines to treat erectile dysfunction 
4. Uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg, or diastolic blood 
pressure ≥ 100 mm Hg)  
5. Type 1 diabetes or type 2 diabetes 
6. A fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5  
7. Recent history of cardiovascular disease (e.g., myocardial infarction or stroke within the 
past 6 months), congestive heart failure, or heart block greater than first degree 
8. Clinically significant hepatic or renal disease  
9. Thyroid disease not controlled 
10. History of malignancy (except for non-melanoma skin cancer). (Applicants, however, 
who have been free of disease for 5 years or more are potentially eligible.) 
11. Severe valvular heart disease (i.e., stage c, as defined by 2014 AHA/ACC guidelines) 
12. Use of medications known to induce significant weight loss/gain, including chronic use 
of oral steroids 

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13. Psychiatric hospitalization within the past 6 months 
14. Self-reported alcohol or substance abuse within the past 12 months, including at-risk 
drinking (current consumption of ≥ 14 alcoholic drinks per week) 
15. Loss of ≥ 10 lb of body weight within the past 3 months 
16. History of (or plans for) bariatric surgery 
17. Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity 
(e.g., swimming) 
18. Any serious or unstable medical or psychological condition that, in the opinion of the 
investigator, would compromise the patient’s safety or successful participation in the 
study 
Key Inclusion Criteria to be randomized to the 52-week weight loss maintenance study: 
 
1. Participants must have lost ≥ 5% of initial weight in the group lifestyle modification 
program 
2. Participants must have a BMI ≥ 30 and ≤ 55 kg/m² or have a BMI ≥ 27 kg/m² with a 
obesity-related co-morbid condition 
3. All other inclusion/exclusion criteria from the 14-week group lifestyle modification 
program apply for participants in the 52-week weight loss maintenance study. 
 
6. STUDY PROCEDURES 
 
6.1 Screening Procedures  
 
All applicants will be screened by phone to determine whether they potentially meet eligibility 
criteria. We will obtain a waiver of written documentation of consent for the telephone screen. 
Those who remain interested in the trial will be scheduled for an in-person interview. The 
Weight and Lifestyle Inventory (WALI),36 a paper-and-pencil inventory that assesses general 
eating and lifestyle behaviors and the Beck Depression Inventory (BDI) will be mailed to eligible 
participants following the phone screen and completed by them prior to their screening/informed 
consent visit. (All patients and subjects at our Center complete the WALI and BDI to facilitate 
their initial interview.) The in-person interview will be conducted by a psychologist, who will 
obtain informed consent and evaluate participants’ behavioral eligibility (i.e., willingness and 
appropriateness to participate). This will include our assessment of the applicant’s mood (as 
measured by interview and the BDI) and suicidality (including history of suicidal ideation and 
behavior, as assessed at screening by interview and the Columbia-Suicide Severity Rating Scale).  
 
Participants who remain interested and pass this portion of the assessment will proceed to meet 
with the study’s nurse practitioner or physician, who will obtain a medical history and conduct a 
physical examination to determine medical eligibility. Persons who continue to remain eligible 
will proceed to have an electrocardiogram (EKG) and fasting blood test to determine that final 
eligibility criteria are met.  Safety screening labs will include a complete blood count (CBC), 
comprehensive metabolic panel (CMP), lipid panel, hemoglobin A1c, insulin, high sensitivity C-
reactive protein (hs-CRP), a thyroid-stimulating hormone (TSH) for subjects with a history of 
thyroid disorder, and a urine pregnancy test (for females of child-bearing age).  
 
6.2 Study Visits 

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Screening visit. The following procedures will be completed at the screening visit as discussed 
above: informed consent, medical history, weight, height, waist circumference measurement, 
blood draw, urinalysis, review of medication, full physical exam, electrocardiogram, sitting 
blood pressure and pulse rate, and meeting with psychologist whose assessment will be used as a 
part of determining the subject’s eligibility for the study.  
 
Phase 1: 14-Week Group Lifestyle Modification Program. All participants will complete an 
initial 14-week group lifestyle modification program, designed to induce a loss >5% of initial 
weight.  They will attend weekly group weight loss sessions (of 90 minutes, with 10 to 12 
participants), led by registered dietitians (RDs) or behavioral psychologists. At week 1, they will 
be instructed to consume their usual diet and to record their food intake (i.e., all foods and 
beverages consumed). From weeks 2 to 13, they will be instructed to consume a 1000-1200 
kcal/d diet that provides four servings daily of a liquid shake (Health Management Resources – 
HMR; 160 kcal per shake), an evening meal comprised of a frozen food entrée (250-300 kcal), 
with a serving of fruit and a salad. Another serving of fruit will be permitted after dinner, 
providing a diet of approximately 1000-1200 kcal/day. All HMR products will be provided free 
of charge. Participants will be responsible for purchasing frozen food entrees and other foods.  
Beginning at week 6, participants will be encouraged to gradually increase their physical activity 
from a minimum of 30 minutes/week (at week 5) to 175 minutes/week at week 14. From weeks 
12-14, participants will be prescribed a re-feeding diet that gradually replaces the consumption of 
shakes with conventional foods, so that they use of shakes will be terminated by week 14. 
Participants will be scheduled for their randomization visit (following a last group session) to 
determine that they have lost 5% or more of initial weight and meet BMI and other study criteria 
for randomization (as determined by a follow up physical examination and other tests). For 
candidates with an obesity-related co-morbidity (e.g., hypertension, hypercholesterolemia, sleep 
apnea, osteoarthritis, etc.), participants will be informed that they will not be able to participate 
in the randomized controlled trial, if they fall below a BMI of 27 kg/m2 during the prior group 
lifestyle modification program. They will be informed when they have reached a BMI of 27.5 
kg/m² and encouraged to slow their rate of weight loss so that that they do not reduce below a 
BMI of 27 kg/m². Falling below a BMI of 27 kg/m² will make them ineligible to participate in 
the randomized controlled trial of lorcaserin. Participants will be informed that they may resume 
active weight loss once the randomized controlled trial has begun. Similar steps will be taken 
with individuals who are free of obesity-related co-morbidities and reach a BMI of 30.5 kg/m² 
during the group behavioral weight loss program. Persons who do not have an obesity-related co-
morbidity must have a BMI > 30 kg/m2 to receive prescription weight loss medication. Persons 
who fail to meet appropriate BMI criteria at the outset of the randomized controlled trial will not 
be permitted to participate. 
 
All group sessions during the Phase I group lifestyle modification program will be conducted at 
the University of Pennsylvania’s Center for Weight and Eating Disorders, following a protocol 
adapted from the Look AHEAD study (developed by Dr. Wadden and colleagues).   
 
Phase 1 Medical Monitoring 
 
Medical screening visit. As discussed previously, persons who are interested in the study will 
undergo a complete physical examination at which height, weight, and blood pressure will be 

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measured.  An EKG will be obtained, as well as a fasting blood test that will include CBC, CMP, 
lipid panel, insulin, hs-CRP, and hemoglobin A1c. For subjects with a history of thyroid 
disorders, a measurement of TSH will be added. For women of childbearing potential, a urine 
pregnancy test will also be performed. Results of these tests will be reviewed by the study 
physician/nurse practitioner to determine whether the participant has any contraindications to 
weight loss or to the use of lorcaserin. These contraindications include but are not limited to: any 
major active kidney, liver, cardiovascular, or cerebrovascular disease; blood pressure ≥ 160/100 
mm Hg; or the use of any medications that significantly affect weight (weight loss or weight 
gain).  
 
Ongoing medical visits and safety measures. During the 14-week group lifestyle modification 
program, vital signs (blood pressure and pulse) will be measured at weeks 1, 2, 4, 6, 8, 10, 12, 
and 14. At week 8 a fasting blood test will be repeated and will include a CBC and CMP. 
Women who are capable of becoming pregnant will undergo another urine pregnancy test at this 
time. In addition, participants will have a brief medical visit (10 minutes) with the study 
physician/nurse practitioner to check for possible complications of early weight loss. Mood will 
be assessed by verbal report throughout the 14-week program. Participants who report significant 
depression or emotional distress will be referred to their primary care provider for further 
evaluation.  
 
Phase 2: 52-Week Weight Loss Maintenance Program. Following randomization to 
medication conditions, all participants will attend group lifestyle sessions, designed to facilitate 
the maintenance of the 5% or greater weight loss achieved during the run-in period. Group 
sessions (10-12 participants) will last 90 minutes and will be offered at post-randomization 
weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. The first two group sessions 
(weeks 2 and 4) will be held in person (on site), after which sessions will alternate between on-
site visits and conference calls.  Telephone delivered lifestyle counseling has been shown to be 
as effective as on-site counseling and is more convenient to participants. All participants will 
have an individual visit with their interventionist at their randomization visit. All treatment 
sessions for the 52-week weight loss maintenance program will be delivered following a 
modified version of the Look AHEAD study. 
 
All participants will be instructed to consume a self-selected diet of conventional foods, 
consistent with their food preferences. Those who weigh < 250 lb will be prescribed 1500-1700 
kcal/day, while those >250 lb will be prescribed 1800-2000 kcal/day. These calorie values are 
consistent with those reported by participants in the National Weight Control Registry. These 
calorie targets are lower than those that would be achieved by subtracting 500-600 kcal from 
patients’ estimated energy requirements and are designed to compensate for obese individuals’ 
underestimation of intake by approximately 40% (as judged by comparison to doubly labeled 
water). Participants will be counseled on how to consume a well-balanced diet and will use a 
calorie counter (provided to them) to meet their calorie targets. 
 
Participants will be instructed in a program of behavioral skills designed to prevent weight regain 
(as delivered by the Look AHEAD study). This will include encouraging participants to increase 
their physical activity to >200 minutes per week (principally through walking or other aerobic 
activity).   
 

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Phase 2 Medical Monitoring 
 
Following the 14-week group lifestyle modification program and immediately prior to 
randomization (to lorcaserin or placebo), participants will complete a second brief history and 
physical examination and undergo another EKG. The study physician/nurse practitioner will 
again confirm that the participant does not have any contraindications to weight loss or to the use 
of lorcaserin. A blood test (which will include a CBC, CMP, lipids, insulin, hs-CRP and 
hemoglobin A1c) and urine pregnancy test (for women of childbearing potential) will be repeated 
at this time.  
 
Following randomization (to lorcaserin or placebo), vital signs (blood pressure and pulse) will be 
measured at weeks 2, 4, 8, 12, 20, 24, 28, 36, 44, and 52. A blood test (which will include a 
CBC, CMP, lipids, insulin, hs-CRP and hemoglobin A1c) and urine pregnancy test (for women 
of childbearing potential) will be repeated at weeks 12, 24, 36 and 52. Participants will attend 
brief medical visits (10 minutes) with the study physician/nurse practitioner at weeks 2, 4, 8, 12, 
24, 36, and 52, with a final visit at week 56 for health assessment after terminating medication at 
week 52. At each medical visit, participant’s response to the medication will be assessed. Study 
subjects will be asked whether there has been any change in their health or medications. They 
also will be asked about their mood or any thoughts of harming themselves through 
administration of the Columbia-Suicide Severity Rating Scale (C-SSRS). In the event of mental 
health events, participants will be referred to the study’s psychologist or psychiatrist for further 
evaluation, if required. For all non-study-related medical events, participants will be referred to 
their own primary care provider  
 
 
6.3 Outcome Measures 
 
Primary outcome measure: body weight.  Two co-primary endpoints will be tested at week 52: 
1) change in body weight (in kg) as measured from randomization to week 52; and 2) the 
percentage of participants in the two groups that (at week 52) maintained the ≥5% reduction in 
body weight achieved during the 14-week group lifestyle modification program.  
 
Body weight will be measured at all clinic visits. However, for purposes of the primary outcome, 
weight will be assessed: at screening (week -14, prior to the group lifestyle modification 
program); at randomization; and at weeks 24 and 52. Weight will be measured on a digital scale 
(to the nearest 0.1 kg) with participants dressed in light clothing, without shoes. Two 
measurements will be taken on each occasion.  
 
Cardiometabolic risk factors will be assessed at screening (week -14, prior to group lifestyle 
modification program); randomization; and weeks 24 and 52.  Fasting blood samples (i.e., 
following an overnight fast) will be drawn on each occasion and assayed for CMP,CBC, lipid 
panel, , insulin, hs-CRP and hemoglobin A1c. (Samples will be analyzed by Quest Diagnostics.) 
Blood pressure and pulse will be measured on each occasion using an automated monitor 
(Dinamap, model 9300). Two readings will be taken on each occasion (at 1-minute intervals), 
after participants have been seated for at least 5 minutes. Waist circumference (measured 
horizontally halfway between the lowest rib and the top of the hipbone) to the nearest 0.1 cm will 

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be assessed on the same schedule. Two waist measurements will be obtained at each assessment 
visit. 
 
Mood, quality of life, weight bias, eating behavior, sleep, stress/fatigue, and physical 
activity. Mood will be assessed on the same schedule as the primary outcome using the PHQ-9 
and at each medical visit using the C-SSRS. Quality of life will be assessed on the same schedule 
as the primary outcome using SF-36 and IWQOL-Lite. The experience of weight bias will be 
evaluated by the Weight Bias Internalization Scale, the Experiences of Weight Bias questions, 
the Stigmatizing Situations Inventory, the Causal Attributes for Obesity scale, and the Everyday 
Discrimination Scale. Cognitive restraint, disinhibition, and hunger will be evaluated at the same 
time, using the Eating Inventory (EI) and visual analogue scales. Binge eating will be assessed 
by the Eating Disorder Examination-Questionnaire (EDE-Q). Food addiction will be measured 
using the Yale Food Addiction Scale, food cravings by the Food Craving Scale, and stress-
related eating by the Eating and Appraisal Due to Emotions and Stress Questionnaire. 
Mindfulness while eating will be assessed by the Mindful Eating Questionnaire and the 
Philadelphia Mindfulness Questionnaire. Stress will be assessed by the Perceived Stress 
Questionnaire, fatigue by the Fatigue-Short Form, and sleep by the Pittsburgh Sleep Quality 
Index and Berlin Sleep Questionnaire. Physical activity will be assessed by the Paffenbarger 
Physical Activity Survey.  The third cohort of participants will have the option of completing the 
Experiences of Weight Bias questions, Weight Bias Internalization Scale, and Causal 
Attributions for Obesity Scale a second time 1 week after the initial administration to assess the 
test-retest reliability of these measures. 
 
Safety Measures: 
 
Phase 1 Risks 
The risk of adverse medical or psychiatric events should be minimized by the careful screening 
procedures to be used. The principal risks during the group lifestyle modification program 
include: 
 
Hypoglycemia. Hypoglycemia may occur during periods of calorie restriction and weight loss. 
Participants will  be instructed what to do if they experience symptoms of hypoglycemia.  
 
 
Risk of gallstones. Rapid weight loss may increase the risk of gallstones. The risk of gallbladder 
disease will be reduced by limiting weight loss to no more than 3 pounds per week for 3 
consecutive weeks.  
 
Blood draw. Risks of drawing blood include pain, bruising at the puncture site, swelling, feeling 
faint or lightheaded, and rarely infection. 
  
Phase 2 Risks 
The risks associated with the use of lorcaserin will be minimized by re-screening participants 
prior to randomization and by the inclusion of 7 brief medical visits during the 52-week study. 
Subjects will be asked at each medical visit if they have experienced any changes in their health. 
The principal risks associated with lorcaserin include: 
 

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Serotonin syndrome. Study participants will be instructed to avoid taking other serotonergic 
drugs to avoid the occurrence of this adverse event. Treatment with lorcaserin will be 
immediately discontinued if a subject experiences symptoms of serotonin syndrome, such as 
mental status changes, autonomic instability (e.g., tachycardia, labile blood pressure, 
hyperthermia), and/or neuromuscular aberrations (e.g.,hyperreflexia, incoordination).  
 
 
 
Blood count changes. Blood test abnormalities that have been reported with the use of 
lorcaserin include decreases in lymphocyte counts and in hemoglobin. In clinical trials of at least 
1-year duration, lymphocyte counts were below the lower limit of normal in 12.2% of patients 
taking the drug, compared with 9.0% of placebo patients. Hemoglobin was below the lower limit 
of normal in 10.4% of patients taking the drug, compared with 9.3% of placebo patients. During 
this study, participant will have regular CBC checks to monitor for any changes. The study 
physician will make a clinical decision as to the whether lorcaserin should be discontinued in any 
subjects who experience blood test abnormalities.  
 
Prolactin elevation. Prolactin levels were found to be higher in lorcaserin than placebo patients. 
Lorcaserin moderately elevates prolactin levels. In a subset of placebo controlled clinical trials of 
at least one year in duration, elevations of prolactin greater than the upper limit of normal, two 
times the upper limit of normal, and five times the upper limit of normal, measured both before 
and 2 hours after dosing, occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients and 
4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively. Participants will be advised to 
contact their PCP if they have symptoms of prolactin excess (breast enlargement and tenderness 
or milk discharge from the breast). The study physician/nurse practitioner will make a clinical 
decision as to whether lorcaserin should be discontinued in any subjects who experience 
symptoms of prolactin elevation. 
 
Psychiatric disorders. Some drugs that target the central nervous system, including lorcaserin, 
have been associated with depression or thoughts of suicide. Events of euphoria, hallucination, 
and dissociation were seen with lorcaserin at supratherapeutic doses in short-term studies. In 
clinical trials of at least 1-year in duration, 6 patients (0.2%) treated with lorcaserin developed 
euphoria, as compared with 1 patient (<0.1%) treated with placebo. Doses of lorcaserin should 
not exceed 10 mg twice a day. Persons who have a history of suicide attempts or active suicidal 
thoughts should not take lorcaserin. Any subject who develops a psychiatric disorder such as 
euphoria, hallucination, dissociation, depression or thoughts of suicide will be instructed to 
discontinue lorcaserin and referred to their PCP for evaluation. 
 
Cognitive impairment. Impairment in attention and memory, as well as confusion, sleepiness, 
and tiredness has been associated with lorcaserin. In clinical trials of at least one year in duration, 
impairments in attention and memory were reported adverse reactions associated with 1.9% of 
patients treated with lorcaserin and 0.5% of patients treated with placebo, and led to 
discontinuation in 0.3% and 0.1% of these patients, respectively. Other reported adverse 
reactions associated with lorcaserin in clinical trials included confusion, somnolence, and fatigue  
Participants will be advised to use caution when operating machinery, including cars, until they 
are certain that the medication is not affecting them adversely. If subjects experience cognitive 

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impairment that does not improve and/or is severe, the study physician will evaluate whether the 
subject should be discontinued from lorcaserin.  
 
Valvular heart disease. The use of lorcaserin may be associated with valvular heart disease, In 
clinical trials of 1-year duration, 2.4% of patients receiving lorcaserin and 2% of patients 
receiving placebo developed valvular regurgitation at 1 year.  Participants will be advised to seek 
medical attention if they experience any symptoms of shortness of breath or leg swelling. 
Subjects found to have valvular heart disease after starting lorcaserin will be discontinued from 
the drug. 
  
Priapism. Priapism (painful erections greater than 6 hours in duration) is a potential 
effect of 5-HT2C receptor agonism. In clinical trials, priapism occurred 0.1% in subjects taking 
lorcaserin compared to 0.1% in placebo-treated subjects. There is limited experience with the 
combination of lorcaserin and medication indicated for erectile dysfunction (ED). In this study, 
men taking medications for ED will be excluded. Subjects who have an erection lasting longer 
than 4 hours, whether painful or not, will be advised to immediately seek emergency medical 
attention and to discontinue lorcaserin. 
 
Reproductive risks. The use of lorcaserin may pose risks to pregnancy and/or an unborn baby. 
Therefore, participants are advised not to get pregnant while in the study.  And women of child 
bearing potential will be required to follow a study-approved method of birth control while 
participating in the study. Adequate birth control in this study is the use of double barrier 
methods (condom with spermicide or diaphragm with spermicide), stable hormonal 
contraception, intrauterine device, abstinence, or tubal ligation. In addition, the study medication 
may have unknown risks to breast-fed babies. Therefore, study participants are instructed not to 
breastfeed while taking the study drug. Should a female subject become pregnant while in the 
study, she will be discontinued from lorcaserin and the weight loss intervention. The subject will 
be asked to report the outcome of the pregnancy to the study staff (e.g. termination, birth 
outcome).  
 
Unforeseen risks. Such risks include allergic reactions to medications. In addition, there may be 
other risks associated with lorcaserin that have not been identified. If additional risks are 
identified during the study, study participants will be informed about these risks by the study 
team.   
 
 
7. STATISTICAL ANALYSIS 
 
Power analysis.  There are two primary intention-to-treat (ITT) contrasts based on a longitudinal 
data analysis design (weight measurements at 0, 24, and 52 weeks). The primary endpoint is 
change in body weight (in kg), as measured from randomization to week 52. The co-primary 
endpoint is the percentage of participants in the two groups that, at week 52, maintained the ≥5% 
reduction in body weight achieved during the 14-week group lifestyle modification program. 
    
We predict a difference in weight change between the two groups (from randomization to month 
12) of 3 kg (SD=5.0, ICC=0.80). We anticipate mean weight changes at week 52 of "0” kg for 
lorcaserin and "+3" kg for placebo.  (This is a conservative prediction; we believe that lorcaserin 

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treated participants may lose a mean of 1-2 kg, while those treated by placebo may gain 4-5 kg. 
Estimates of mean weight regain for placebo-treated participants are based on prior studies we 
and others have conducted, while estimates for lorcaserin are based on findings from studies of 
sibutramine and liraglutide that have used similar run-in designs.) Furthermore, we predict that 
80% of the lorcaserin participants will have maintained the ≥5% reduction in body weight from 
randomization through the 52 week assessment, as compared to only 50% of the placebo group.  
Based on the Holm’s procedure that adjusts for multiple comparisons,37 the smaller of the two p 
values resulting from analyses of our two primary contrasts will be compared at alpha equal to 
0.025 and, if significant, the other contrast will be evaluated at 0.05. Consistent with this form of 
Type I error control, our primary approach for estimating study power is “the probability of at 
least one significant contrast.” 
 
Using a sample size equation for longitudinal clustered samples,38 a randomization  sample size 
of 68 participants in placebo and 68 participants in the lorcaserin treatment group (total sample: 
136) provides over 80% power to detect the two primary  contrasts to be statistically significant 
at the Holm’s adjusted alpha levels noted above. This estimate allows for 20% attrition during 
the 52-week randomized trial, resulting in approximately 54 treatment completers in arm.  The 
ITT longitudinal statistical design will further improve power by allowing the inclusion of 
available data for non-completers and the adjustment of possible variance reducing baseline 
covariates.   All secondary analyses will be considered exploratory and evaluated at the alpha = 
0.05 level. The power analysis was conducted using PASS 11.39  
 
Statistical plan: preliminary analyses.  All data will first be assessed by the data management 
staff, for missing data and out-of-range values with basic statistical procedures such as univariate 
statistics (i.e., means, standard deviations, ranges, frequencies, proportions, percentiles) and 
graphs, such as histograms, box and whisker plots, scatter plots and Q-Q plots. In addition, plots 
will be produced of individual and average trajectories of all repeated measures over time 
according to assigned treatment.   All questions of data quality and integrity will be investigated 
before any statistical modeling is conducted.  
 
Next, a preliminary analysis of all outcome and baseline demographic variables will be 
performed to test for differences in baseline measures between the randomized groups. The test 
of the adequacy of randomization will consist of tests of differences between the treatment 
conditions to see if the baseline variables are equally distributed between them. These baseline 
comparisons will be based on: t-tests or Wilcoxon rank sum tests for continuous variables, 
depending on the symmetry of the distributions; on Chi-square, Fisher’s Exact or logistic 
regression for binary or ordinal variables; and on Poisson log-linear regression for count data. If 
imbalances are found at baseline, then the relevant variables will be treated as confounders in the 
post study analyses. 
 
Primary analysis.  To test the principal hypothesis that patients randomized to lorcaserin (with 
lifestyle intervention) will achieve significantly better maintenance of lost weight than those 
assigned to placebo (with lifestyle intervention, as measured by weight change (in kg) from 
randomization to week 52, a nested (cluster) mixed model will be fit utilizing the mixed 
procedure in the statistical software package SAS, version 9.3.  An intention-to-treat (ITT) 

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analysis will fit an unstructured covariance matrix to adjust of the repeated measures data 
clustered with the individual participant.  In addition, these models will contain the following 
fixed effects: main effect for change from baseline to each follow-up visit (weeks 24 and 52), 
group (2 conditions assuming intent-to-treat analyses), and interaction between the visit and 
group indicator variables. Tests of these interactions will correspond to tests of ITT differences 
among the treatment conditions.  Estimates and confidence intervals for these group differences 
will be derived from interaction and main effects parameters of the models.  The primary focus 
with be on the 52 week comparison. For the co-primary comparison of the percentage of 
participants in the two groups that, at week 52, maintained the ≥5% reduction in body weight 
achieved during the 14-week group lifestyle modification program, we will use generalized 
estimating equations (GEE) within the GENMOD procedure in SAS (2011) to fit population-
averaged logistic models assuming the binomial distribution. As noted previously, we will use 
the Holm’s procedure to control the overall alpha for the two sets of comparisons (for the 
continuous and dichotomous outcomes).     
 
 All randomized participants will be included in the primary intention-to-treat (ITT) analysis. A 
modified ITT analysis also will be conducted which includes only those participants who receive 
at least one dose of medication and provide at least one post-randomization measurement of 
body weight. A per protocol analysis will be conducted that includes only those participants who 
provide a measurement of body weight at week 52 (with a window of +4 weeks). All randomized 
participants will be included in the safety analysis. No interim analyses are planned (in order to 
maintain full power for the end-of-study comparisons). 
 
Secondary analyses. Similar analytic strategies will be employed for all other continuous 
secondary efficacy endpoints, as well as for binary (dichotomous outcomes; i.e., percentage of 
participants who achieve different criterion weight losses).  
For the logistic model, differences will be presented as odds ratios with confidence intervals; for 
linear model, the least squares means and standard errors will be presented with confidence 
intervals. 
 
Missing data. All analyses will be conducted using the ITT principle, in which all available data 
on all randomized patients are included.  This approach minimizes bias if participants drop out of 
the intervention for different reasons. Assuming adequate fit of the mixed effects models to the 
data, the proposed nested random effects models are the most robust to missing data assumptions 
among standard longitudinal models that analyze all subjects regardless of how many post-
randomization visits are missed. The following missing or unbalanced data scenarios can be 
accommodated by such models: attrition (drop out), missed interim visits, and missing covariate 
data where a subject is interviewed but data are missing on covariates of interest.  All three types 
of missing data are handled by way of maximum likelihood under the proposed mixed effects 
models and the missing at random assumption (MAR).  Therefore, we will explore the potential 
bias of missing data by comparing completers and non-completers to see if they differ 
systematically on values of non-missing variables. There are many ways to assess the assumption 
of MAR. We will consider imputing missing endpoint data using multiple imputation techniques, 
fitting selection models (e.g. MNAR), and fitting pattern mixture models. 
 
 

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8. SAFETY AND ADVERSE EVENTS 
 
At each contact with participants, the study personnel will seek information on adverse events by 
specific questioning and, as appropriate, by physical examination. Information on all adverse 
events will recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results will be recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period will be recorded. The clinical course of 
each event will be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause. Serious adverse events that are still ongoing at 
the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported immediately. All serious 
adverse events will be reported to the IRB within 10 working days.  
 
10. DATA HANDLING AND RECORD KEEPING 
 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 
 Protected health information (PHI) collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of research participants to revoke their authorization for use of their PHI 
 View of PHI will be limited to individuals at the University of Pennsylvania directly 
involved in the study. The company donating the study product will not have access to 
PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For participants who have revoked authorization to collect or use PHI, attempts 
will be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
 
11. STUDY MONITORING, AUDITING, AND INSPECTING 
 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 

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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
 
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