Efficacy and Mechanisms of Naltrexone+Bupropion for Binge Eating Disorder
Phase: PHASE2
Conditions: Binge-Eating Disorder
Sponsor: Yale University

 
NCT03539900 
 
Efficacy and Mechanisms of Naltrexone+Bupropion for Binge Eating Disorder 
Document date: 4/4/2022 

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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2016-1)
Protocol Title: Efficacy and Mechanisms of Naltrexone+Bupropion for Obesity and Binge Eating
Principal Investigator: Carlos M. Grilo, Sherry McKee
Version Date: 3/10/2022    Version: 12
(If applicable) Clinicaltrials.gov Registration #: NCT03539900
SECTION I: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
PRIMARY AIM 1. To conduct a double-blind, placebo-controlled parallel group study to evaluate the efficacy 
of naltrexone HCI and bupropion HCI (NB) versus placebo in patients with binge-eating disorder (BED), 
stratified by obesity status (n=50 per cell, n=200 total).
Hypothesis 1.1. We hypothesize that NB will be superior to placebo for reducing binge eating among patients 
with BED.  
Hypothesis 1.2. We hypothesize that NB will be superior to placebo for reducing weight among BED patients 
with obesity.
Hypothesis 1.3. We will examine whether BED patients with and without obesity derive differential benefit of 
NB versus placebo on reducing binge eating (i.e., does obesity moderate outcomes).
PRIMARY AIM 2. To evaluate correlates and possible mechanisms underlying the effect of NB on binge eating 
among all participants (n=50 per cell, N=200 total). To evaluate the effect of NB on hypothalamic 
melanocortin and brain reward systems, eating behavior will be assessed with an established human 
laboratory paradigm designed to evaluate the ability to resist eating preferred high-caloric food and 
subsequent over-eating. We will evaluate potential mechanisms including eating peptides (leptin, ghrelin) 
involved in both homeostatic and hedonic aspects of eating, as well as food craving, mood, hunger, and 
control over eating. 
Hypothesis 2.1. We hypothesize that potential medication-related changes in eating behavior, eating peptides 
and craving assessed in the laboratory will mediate clinical outcomes during the 12-week treatment 
period (i.e., rates of binge eating).
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Hypothesis 2.2. We hypothesize that NB versus placebo will increase the ability to resist eating preferred high-
calorie food, and will reduce overall calorie consumption in patients with BED. 
Hypothesis 2.3. We will examine whether BED patients with and without obesity derive differential benefit of 
NB versus placebo with regards to their ability to resist eating or calories consumed (i.e., does obesity 
moderate outcomes).
EXPLORATORY AIM 3. To assess eating and drinking behavior, food craving, and mood ‘in the field’ in a subset 
of participants (n=60). 
2.
Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities.  
September 2017 – September 2024
3.
Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
Binge-eating disorder (BED) is a prevalent, refractory, and serious health problem, with national estimates 
identifying that 2.6% of adults meet criteria for BED [1]. With the recent inclusion of BED as a formal DSM-5 
diagnosis [2], there has been increased attention on identifying effective pharmacotherapies for this disorder. 
This application focuses on evaluating the therapeutic potential of naltrexone combined with bupropion for 
BED.
Recognized as a serious problem by Stunkard [3], only recently has BED become a research focus and 
established as a formal diagnosis in the DSM-5 [2]. BED is defined by recurrent episodes of binge eating 
without compensatory weight control methods that characterize bulimia nervosa. Binge eating is defined as 
eating an unusually large amount of food given the context coupled with a subjective sense of loss of control 
and diagnosis requires binge eating to be associated with marked distress [4]. Epidemiologic studies have 
found that BED is more prevalent than the other two formal eating disorders [5]. Estimates of BED are higher 
in adults with obesity (8%) and are much higher in most clinical settings [6, 7]. Of adults with current BED 
diagnosis, 42% meet criteria for obesity (BMI > 30) whereas 58% do not meet criteria for obesity (BMI < 30) 
[8]. BED is strongly associated with obesity, with rates of BED disproportionately increasing with increasing 
BMI. Adults with BED are 4 to 10 times more likely to present with BMI’s of 30 or 40 or more, respectively [8]. 
BED may be a contributor to the development of obesity [9] and associated metabolic problems [10] in 
vulnerable individuals. 
Compared to other eating disorders, BED is prevalent across gender and ethnic/racial groups [11]. The 
prevalence of BED in the National Co-morbidity Survey Replication [1] was 3.5% among women and 2.0% 
among men. BED has diagnostic validity [12], is a stable construct [13], differs from other eating disorders and 
obesity [14-16], is strongly associated with elevated risk for psychiatric, and psychosocial problems [5, 15, 17, 
18]. BED is associated with substantially increased risk of several chronic health conditions including cardio-
metabolic disorders, musculoskeletal disorders, pain, and ulcers [8, 19], even when adjusting for BMI [10].
Overall, several medications have short-term efficacy relative to placebo [20] and certain psychological 
treatments have efficacy [21] with important advantages over medication (alone or in combination) [20]. 
Pharmacotherapy for BED has received research attention, albeit nearly all RCTs have been of short duration 
and without follow-up period to establish durability [20, 22, 23]. Critical review and meta-analysis show that 
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several drugs – working through varied mechanisms – have short-term efficacy relative to placebo for 
reducing binge eating and produce weight loss ranging from modest to none [20]. Placebo-controlled trials of 
anticonvulsants topiramate and zonisamide [24-26] have reported effects for reducing both binge-eating and 
weight (average weight loss of roughly 3-4 kg compared to placebo), but have also shown high dropout and 
frequent adverse events that become near-universal and troubling with longer use [27]. SSRI antidepressants, 
initially regarded as a potential treatment strategy [e.g., 28] are characterized by small effect sizes relative to 
placebo [20], produce no weight loss at all [29] and are inferior to CBT [29, 30]. 
Lisdexamfetamine dimesylate (LDX) for BED. An important development was the FDA approval in January 
2015 of a CNS stimulant, LDX, for the treatment of moderate-to-severe BED. Approval was based on findings 
from an integrated series of studies funded by the manufacturer. The phase II RCT demonstrated that 50mg 
and 70mg were superior to placebo [31, 32] for reducing binge-eating days and reported binge-eating 
abstinence rates of LDX versus placebo (Study 1: 40% versus 14%; Study 2: 36% versus 13%) at the end of the 
11-week treatments. Importantly, no longer-term follow-up are presently available. 
We are not using LDX for several reasons. The binge remission outcomes for LDX at 11-weeks [31] are less 
robust than those reliably produced by BWL for BED, and BWL outcomes are durable through 12-months 
post-treatment [33]. Most importantly, although LDX was associated with weight loss (mean 4.9 kg) [32], 
weight loss was examined as a safety measure, not a clinical outcome. The FDA approval and manufacturer 
product labeling included a Limitation of Use highlighting that LDX is not indicated or recommended for 
weight loss. This is because other CNS-stimulant sympathomimetic medications for weight loss have been 
associated with severe cardiovascular problems and the safety and efficacy of LDX for obesity have not been 
demonstrated. 
Pharmacotherapy for Obesity. Sibutramine, which was effective for reducing both binge eating and weight in 
BED [34, 35], was withdrawn from the market in 2010 due to cardiovascular concerns. This left orlistat as the 
sole FDA-approved anti-obesity medication for longer-term use [36], until 2012. Placebo-controlled trials of 
orlistat for BED [37, 38] reported significant yet very modest effects for weight loss, but not for reducing 
binge eating when added to BWL or CBT. A recent RCT testing orlistat combined with BWL reported a 
moderator effect of significantly greater weight loss for orlistat than placebo for obesity without BED, but not 
for obesity with BED [39]. 
The 2012 FDA approval of two new anti-obesity medications (phentermine/ topiramate and lorcaserin) [40, 
41] came after heated debate given significant concerns about limited efficacy and safety profiles, and 
questions about serious medical complications with longer use [40, 41]. The low rates of achieving 5% weight 
loss (less than 30% in all three of the phase III RCTs) was inflated due to the use of completer analyses despite 
the observed high drop-out rates (e.g., 45% in the BLOOM Trial) [42]. The combination phentermine/ 
topiramate had the highest effect sizes for weight loss, but this needs to be considered against the 
unfavorable adverse event and tolerability profile.
Behavioral Treatment for Obesity. Behavioral Weight Loss (BWL) counseling has been evaluated among 
patients with comorbid BED and obesity. BWL, a widely available “generalist” intervention, achieves good 
binge-eating outcomes plus produces modest weight loss over the short-term in persons with BED who also 
have comorbid obesity [43, 44]. BWL for BED in persons with co-morbid obesity outcomes, however, are less 
durable over time [44] and the observed weight losses achieved with BWL for BED appear to be dampened 
relative to those generally reported for BWL for obesity without BED [45, 46]. These results highlight that 
behavioral treatments for patients with BED and comorbid obesity do not produce consistent effects on both 
binge eating and weight loss, identifying a need for further treatment development.  Additionally, many 
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people with BED do not have excess weight or obesity and BWL for “normal weight” persons with BED has not 
been tested. 
A test of NB for patients with BED without obesity is needed and the mechanistic background for NB 
medication supports the rationale for use in BED. The current RCT will test pharmacological treatment 
(without any behavioral intervention) so that findings are more scalable and broadly translatable to generalist 
settings.  The published RCT pharmacotherapy literature for BED consists mainly of med-only vs placebo-only 
trials ranging from 6 to 24 weeks (many are 12 weeks) [23].    
We performed a pilot RCT (HIC# 1409014705) with N=22 patients with BED and obesity and delivered the NB 
pharmacotherapy without concurrent behavioral weight loss. We observed no problems in the conduct of the 
pilot RCT. The pilot RCT found that NB was well-tolerated, reduced the frequency of binge eating, and 
promoted weight loss in the obese patients with BED with moderate effect sizes. Finally, we have an on-going 
recently-funded RCT (HIC# 1506016065) that is examining intensive BWL and NB, alone and combined (i.e., 
balanced 2 x 2 factorial design; thus, some patients also receive NB without BWL) in patients specifically with 
BED with obesity.
NB Pharmacotherapy 
In September 2014, the FDA approved the combination of naltrexone and bupropion to treat obesity 
consisting of the following empirical support from several RCTs performed with obesity (but not BED). The 
putative mechanisms of action are described in Section VI.
Obesity Outcomes. Several large RCTs have reported that NB was effective in promoting significant, clinically-
meaningful weight loss in patients with obesity [47-49]. NB showed greater weight loss than placebo, -6.5 vs -
1.2% [49]; -8.2% vs -2.1% [48], and the following percentages achieving 5% weight loss: 56% vs. 18% [48], 
52% vs. 15% [49]. Apovian, Aronne [50], in a study of 1496 patients with obesity, reported greater weight 
losses relative to placebo (-6.5% vs -1.9% at week 28 and -6.4% vs -1.2% at week 56) and greater likelihood of 
achieving 5% weight loss (56% vs 18% at 28 weeks).
The putative mechanisms of action for the two medications are relevant for binge eating in addition to weight 
loss. Naltrexone, an opioid receptor antagonist, is approved for treatment of alcohol and opioid dependence 
(O’Malley, Sinha, Grilo, et al., 2007). Naltrexone produces weight loss in lab animals but only minimal weight 
losses in most human studies (Malcolm et al. 1985; Billes & Greenway, 2013). Bupropion is thought to 
operate through dopaminergic, noradrenergic, and nicotinic acetyl-cholinergic mechanisms [51-53], may 
target reward processes that drive eating behaviors, consistent with its FDA indication for treating nicotine 
dependence and reduced weight gain during smoking cessation [54, 55]. Bupropion has been found to 
promote weight loss in several obesity RCTs.  Li and colleagues [56], in a meta-analysis of five trials of 
bupropion, reported a mean difference in weight loss of 2.77 kg (CI, 1.1 to 4.5) between bupropion and 
placebo groups at 6 months. White & Grilo (2013) first reported preliminary support for a possible (albeit 
modest) weight loss benefit specifically in obese BED patients (see C.1).
NB was developed to target alterations in the hypothalamic melancortin system and the brain reward system 
(Billes et al., 2014), although the neurobiological mechanisms underlying its efficacy for weight loss are not 
fully understood. Within the hypothalamus, bupropion stimulates hypothalamic pro-opiomelancortin (POMC) 
neurons whereas naltrexone blocks opioid receptor-mediated POMC autoinhibition, resulting in weight loss 
and reductions in energy expenditure as hypothesized downstream effects (Wang et al., 2014). Within the 
reward system, dopamine drives the ‘wanting’ for highly palatable food, whereas the opiate system 
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modulates the ‘liking’ (Billes et al., 2014). Preclinical studies identify that bupropion and naltrexone work 
synergistically on the reward system to reduce food intake (Sinnayah et al., 2007). 
Although NB targets systems highly relevant for those with BED (Simon et al., 2016) and obesity (Jastreboff et 
al., 2013), very little work has examined potential mechanisms of NB in humans. Wang et al., (2014) examined 
responses to food cues in obese women and documented blunted activation in hypothalamic reactivity and 
increased activation in the anterior cingulate, suggesting greater self-control. Within clinical trial 
investigations, NB was associated with self-reported ability to control food intake as this was associated with 
weight loss (Fujioka et al., 2013). There was also mixed evidence that NB reduced food craving, which was 
assessed monthly. The effect of NB on food craving has yet to be assessed in response to actual food cues.
Leptin and ghrelin are involved in both homeostatic and hedonic aspects of eating (Farooqi et al., 2007; Malik 
et al., 2008), and may serve as important biomarkers of NB’s effects on these systems. Leptin mediates 
regulation of energy balance and suppresses food intake, whereas ghrelin is a faster-acting hormone involved 
in the initiation of eating. Generally, obesity is associated with increased and decreased levels of leptin and 
ghrelin, respectively (Klok et al., 2007). However, alterations that occur in the homeostatic and reward 
systems as a result of obesity, and potentially BED, may make these systems less sensitive to appetite 
regulating substances such as leptin and ghrelin. Both leptin and ghrelin have been associated with increased 
neural activation to high-calorie food, food craving, and food intake (Jastreboff et al., 2014; Kroemer et al., 
2012; Skibicka et al., 2012).
4.
Research Plan: Summarize the study design and research procedures using non-technical language that can 
be readily understood by someone outside the discipline. Be sure to distinguish between standard of care vs. 
research procedures when applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
Overview of Study Design
This single-site, proof-of-concept, clinical trial is a double-blind, placebo-controlled, parallel group study to 
test the effectiveness of naltrexone + bupropion (NB) pharmacotherapy in BED patients with and without 
obesity. BED patients with (BMI > 30 and <50) and without obesity (BMI >21.5 and <29.9), will be randomized 
to NB (32 mg/day naltrexone combined with 360 mg/day bupropion) or placebo (n=50 per cell, n=200 total). 
Following eligibility screening and randomization, participants will start a 12-week medication treatment 
period, a treatment period consistent with other BED medication trials (McElroy et al., 2016). Participants will 
have four weeks of up-titration: one tablet daily (Naltrexone 8mg/ Bupropion 90mg; 1 week), then two 
tablets daily (Naltrexone 16mg/ Bupropion 180mg; 1 week), then three tablets daily (Naltrexone 24mg/ 
Bupropion 270mg; 1 week), to reach the full dose of four tablets daily (Naltrexone 32mg/ Bupropion 360mg). 
The dosage will continue for the remainder of the 3 months. Medication will be discontinued at the end of 3 
months, and patients will then be followed 12-months post-treatment to assess the durability of medication 
effects. The primary outcome measure is reduction in binge-eating frequency. 
To evaluate correlates and mechanisms of NB on eating behavior, assessments will occur in the laboratory 
and in the field to optimize internal and external validity. Participants will complete human laboratory 
sessions (“lab sessions”) before the start of medication and then during the final week of the 12-week 
medication period to evaluate the ability to resist eating preferred high-caloric food and subsequent over-
eating. During the laboratory sessions, we will evaluate potential mechanisms including eating peptides 
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(leptin, ghrelin) involved in both homeostatic and hedonic aspects of eating, as well as food craving, mood, 
hunger, and control over eating. Participants who are unable to complete a baseline lab session prior to the 
start of treatment may complete the lab session 4-6 weeks after beginning treatment. We believe that this 
period of time is sufficient to capture medication effects on eating behavior.
Finally, we plan to monitor ambulatory dynamic changes in stress with a wearable biosensor and collect daily 
information regarding eating behavior with self-initiated, scheduled, and random prompts to a smartphone 
‘in the field’ during the first 6 weeks of the 12-week treatment period in a subset of participants (n=15 per 
cell, n=60 total; “Biosensor”). Eating and drinking behaviors will be tracked using an Android smartphone that 
is synced with a smartwatch (Garmin Vivosmart 4) to passively track stress states.  During real-time episodes 
of calorie consumption, participants will be prompted to answer questions delivered to their smartphone 
related to food craving, mood, and stress.
Figure 1. Overview of Study Design
Pre-Screening: Participants responding to recruitment efforts will be screened by telephone. If participants 
prefer to answer some of the pre-screening questions through the Yale Qualtrics system, participants will 
indicate their consent to the recruitment/pre-screening process in the online system. After the initial 
telephone screening, potentially eligible participants will be scheduled for an in-person assessment; 
participants will complete survey measures of eating behaviors and psychopathology and psychosocial 
functioning around the time of the in-person appointment. Potential participants will meet with a research 
assistant who will obtain informed consent and will screen the participant for inclusion and exclusion criteria. 
Participants who provide informed consent and are determined to be eligible will then participate in the study 
as depicted and described in the following paragraphs. See also Figure 1. 
Baseline Assessment: Participants will complete a physical exam, vitals, and routine laboratory blood work 
(including lipid profile, Hb1Ac, and liver function tests) at which time the study physician will review the 
subject’s medical status and medical eligibility criteria. Patients will also have a urine screen for opiates. As 
part of the determination of eligibility, participants will complete two interviews, the MINI International 
Neuropsychiatric Interview-Version 7.0 (MINI) and Eating Disorder Examination (EDE) to generate psychiatric 
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diagnoses and detailed current eating disorder features and diagnoses. Other measures, for safety and 
establishment of baseline values, will also be obtained: BMI, vitals, eating behaviors, mood, and quality of life. 
For a full description of instruments, see “Measures,” which includes a grid depicting when each measure is 
administered. The baseline assessment will occur over 1-2 in-person meetings and is estimated to take a total 
of 2-3 hours in-person. 
Randomization. Eligible participants who agree to participate and provide written informed consent will be 
randomized in equal proportions to one of the two treatments (using blocked randomization with random 
block sizes of 4 and 8 to obviate any secular trends). Gender will be balanced across cells (60% female). We 
will monitor randomization procedure and determine whether any systematic differences in demography 
(age, ethnicity/race) or clinical characteristics (psychiatric co-morbidity) become evident. We will consider 
adjustment to randomization if indicated (Kraemer & Fendt, 1990; Kraemer & Pruyn, 1990). The 
Biostatistician, Brian Pittman, will be responsible for developing the randomization schedule in conjunction 
with the Investigational Drug Pharmacy (IDS), at Yale-New Haven Hospital. The IDS will randomize participants 
to medication groups. Research study staff (clinicians and outcomes assessors) and participants will all remain 
blind to the medication condition.
Treatment Protocol for Naltrexone/Bupropion (NB) Pharmacotherapy. Medication will be prescribed at 
recommended doses per FDA-approval for obesity. NB medication will comprise naltrexone sustained-release 
(SR, 32 mg/day) combined with bupropion SR (360 mg/day) taken daily (8 mg naltrexone/90 mg bupropion in 
each tablet/capsule, two of which will be taken twice daily; both conditions will have the same frequency). 
Following regimens in previous RCTs, a dosing escalation approach will be used, beginning with a quarter of 
the full dose and increasing it weekly until the full dosing is achieved at week 4 (Greenway et al., 2010; 
Wadden et al., 2011). This dosing will continue for the remainder of the trial unless the patient develops 
intolerable side effects. If such occur, the physician may reduce the dosing to achieve tolerability. If the 
patient cannot tolerate the medication, has adverse effects, or is non-compliant with medication for > 7 
consecutive days, s/he will be discontinued from the medication arm. For all participants taking medication 
for greater than 4 weeks, a 7-day taper will be provided. Physician/medication-management visits will be brief 
(10 minutes) and will focus on compliance with dosing and evaluating side effects. These visits will occur twice 
during first month and monthly thereafter unless clinical concerns require additional contacts. At the one-
month treatment visit and at the end of treatment, patients will have their blood drawn to measure hepatic 
function for safety. Blood draws will occur either at Quest Diagnostics, at the Hospital Research Unit, or at the 
Church Street Research Unit. After the 12-month follow-up, patients will be informed (by research 
pharmacist) whether they were on NB or placebo. Medication double-blind will be maintained for the 
investigators and assessors until all participants have completed final 12-month follow-up assessments. 
 
Monitoring and enhancing medication compliance. In addition to physician visits, several procedures will be 
used to monitor and enhance medication compliance including drug packaging, reminder calls, pill counts, 
and plasma trough medication levels. As we have done in prior studies, medication compliance will be 
assessed with pill counts. Medication will be dispensed in pill bottles; adverse events will be assessed at each 
appointment. Medication compliance will also be monitored through evaluation of a plasma level of 
naltrexone, 6-beta-naltrexol, and bupropion at weeks 4 and 12. Importantly, we plan to explore the 
relationship between compliance and study outcomes.
Withdrawal from Treatment and Other Treatments. Withdrawal/attrition from treatments will be examined. 
Use of other treatments during study will be assessed and considered in analyses. Patients will be asked 
about all forms of treatments during major assessments. We have considered criteria for removal of patients 
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from the study, including worsening depression, suicidal ideation or binge eating, or failure to comply with 
medication. Previous experience suggests that worsening clinical status is rare; in such cases, Dr. Grilo and 
study physician would determine whether to remove the person from the study and provide referrals. 
Procedures for Modeling Cue-Induced Eating Behavior.
Each participant will complete two laboratory sessions, the first scheduled prior to starting medication, and 
the second at the end of medication treatment (week 11-14). This pre-post evaluation by medication group 
will provide a powerful test of medication effects. Alternatively, if the pre-treatment laboratory session 
cannot be schedule prior to the beginning of treatment, participants may complete the session around one 
month of treatment (week 4-6). If we are unable to reschedule at the HRU/CSRU, the lab session will take 
place at 2 Church Street South in dedicated lab rooms in Dr. McKee’s research space. Our previous eating 
study (HIC# 0909005678, McKee) took place in this setting and was very successful. There will be no blood 
collected throughout the lab session if it occurs at 2 Church St South, but baseline samples will be obtained 
on the 4th Floor YCCI unit. All other lab procedures will remain the same. Participants will not be excluded 
from the treatment study if they are not willing to do the lab sessions, or if they are not able to be scheduled 
for the lab sessions. Research procedures related to the treatment study (e.g., blood draws for liver function, 
lipids, and metabolic function) will still be drawn if lab sessions are not completed. 
Laboratory sessions will be completed at the Hospital Research Unit (HRU) of the Yale Center for Clinical 
Investigation (YCCI) located at Yale-New Haven Hospital or the Church Street Research Unit (CSRU) at 2 
Church Street South. Participants will be instructed not to eat past 10:00pm the night before the laboratory 
session. They will arrive at the HRU/CSRU at 7:30am. At the start of the lab session, participants will have an 
IV cannula inserted and complete the baseline assessments listed in Table 1. Participants will then receive 
breakfast to standardize time since last food consumption. Breakfast will be a breakfast bar that is 
approximately 150 calories provided by the Research Team. Participants will then be food deprived for the 
next 3 hours. Based on our prior work, this length of food deprivation is sufficient to increase food craving. 
After 3 hours of food deprivation, participants are presented with preferred high-caloric snacks. Participants 
will be asked to take their study medication prior to the second lab session. Scheduling is limited to 
HRU/CSRU and participant availability. 
During a prior appointment, participants are presented with an extensive list of high-caloric salty (potato 
chips, peanuts) and sweet snack foods (cookies, chocolate), and are asked to select their top three salty and 
sweet options for a total of six options. During the lab session, participants will be presented with a 
standardized amount of each of their six preferred high-caloric foods. The snacks will be portioned to 750 
calories of each (approximately 4-5 servings of each item). The weight of the food will be assessed at the start 
and end of each session, and calories consumed will be calculated from baseline evaluations of calories per 
gram. Each participant will receive the same presentation and amount of food across the two sessions. 
Following the presentation of food, participants are then told that they can start eating at any time they wish 
over the next 3 hours. We model the ability to resist eating over a 3-hour period, to provide sufficient time to 
capture the effect of the high-caloric snack food triggering eating. Participants are informed that for each 
minute that they can resist eating, they will receive monetary compensation. The amount of money earned 
over the 3 hours starts at $0.35 per minute, and reduces by a penny every 5 minutes. By 180 minutes, the 
compensation has reduced to $0 per minute. Participants are provided this information in table format during 
the laboratory session. If a participant resists eating for the entire 3 hours, they will earn a total of $31.50. 
Participants will be videotaped and wear a smartwatch (wearable Biosensor) synced to a research 
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smartphone during the eating session. The data will be coded and provide information about how fast 
participants eat and the order in which foods are selected. 
When participants can no longer resist and decide to start eating, latency to eat will be recorded in seconds. 
Participants may eat as much as they wish until the end of the 3-hour ad-lib period. Measures of leptin, 
ghrelin, food craving, hunger, mood, and vitals will be assessed throughout the laboratory procedure (see 
Table 1). At the end of the period, participants will remain in the laboratory for an additional 1.5 hours to add 
a response cost if they chose not to consume any food during this period. In other words, they are not 
immediately able to leave the session to go eat. 
Table 1: Procedures and assessments for laboratory sessions (also see Table 2).
PERIOD
TIMING
PROCEDURES
7:30am
Urine pregnancy screen, breath alcohol level, CO level, height, weight, vitals, 
mood, food craving, hunger. IV inserted: Estradiol/progesterone (females only), 
liver function, lipids, glucose, insulin, and HbA1c, and overnight fasting levels of 
leptin, ghrelin. Lab 2 Only: Med level, liver function, Lipids, glucose, insulin, and 
HbA1c levels.
Baseline
8:00am
Standardized breakfast (no access to food until 11:00am = 3hours of food 
deprivation)
9:00am
Mood, food craving, hunger, vitals
Deprivation
10:00am
Mood, food craving, hunger, vitals
10:30am
Baseline 1: leptin, ghrelin
10:45am
Baseline 2: leptin, ghrelin
11:00am
Participant presented preferred high-caloric foods. Participant may initiate ad-lib 
eating session or earn money based on de-escalating schedule of reinforcement 
over next 180 minutes
11:05am
Leptin, ghrelin, mood, food craving, hunger, vitals
Food 
Presentation
11:15am
Leptin, ghrelin, mood, food craving, hunger, vitals
Ad-lib 
Period
11:30am
12:00pm
12:30pm
1:00pm
1:30pm
2:00pm
Leptin, ghrelin, mood, food craving, hunger, vitals will be repeated every 30 
minutes during the ad-lib period
**from 11:05am to 2:00pm, whenever the participant decides to ‘give in’ and 
start eating, we will collect leptin, ghrelin, mood, food craving, hunger, vitals to 
capture the decision point to eat (before eating starts)
2:45pm
Mood, food craving, hunger, vitals
3:20pm
Mood, food craving, hunger, vitals
Wait Period 
& Discharge
3:30pm
Discharge
Procedures for Evaluating Naturalistic Eating Behavior and Stress with Wearable Biosensors.
Garmin Activity Tracker (Biosensor): We are collaborating with Dr. Deepak Ganesan (UMass) to evaluate 
ambulatory stress and eating behavior during the first 6-weeks of the treatment phase. We are currently 
using the same system to monitor stress and alcohol consumption (HIC#2000023970; PI, McKee) and it has 
been adapted to monitor stress and eating behavior. During the first 6-weeks of the treatment phase, we will 
assess ambulatory dynamic changes in stress with a wearable biosensor and collect daily information 
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regarding eating behavior with self-initiated, scheduled, and random prompts to a smartphone. We will 
provide participants with the wearable biosensor (Garmin Vivosmart 4) and an Android cell phone to use that 
has the app installed where they will respond to daily prompts. If the equipment is not available when a 
participant is to start the treatment phase, they will not complete the Biosensor component.   
Monitoring Stress Levels. To monitor ambulatory stress levels, we will use Garmin bands. These bands provide 
a ‘stress score’ (range 1-100) with a 3-minute granularity. The algorithm is proprietary, but Garmin 
acknowledges that one of the primary factors in the algorithm is heart rate variability (HRV). HRV is the beat-
to-beat variation in heart rate, which has been shown to be associated with emotion regulation and likely 
contribute to binge eating101. We have shown that stress and substance use produce dynamic changes in 
HRV102-104, and that HRV may be used as a stress indicator. With values provided every 3 minutes, we can 
model how dynamic changes in HRV are predictive of binge eating. We also plan to evaluate how location 
(e.g., GPS) affects stress levels and subsequent eating behavior. The Garmin band also provides daily metrics 
on steps, distance, heart rate, sleep duration, and sleep level classification. Access to this data is through a 
Garmin service to academic researchers https://developer.garmin.com/health-api/overview/. Data 
obtained from bands will be continuously transmitted to the mHealth Core Facility at UMass.
Monitoring Eating Behavior. During the 6-week monitoring period, we will monitor eating behavior in three 
ways through an app on the Android smartphone. 1) Participants will complete daily diaries every evening at 
10PM or when participant initiates “End of Day” which assess eating throughout the day. Participants will 
answer questions about their daily eating pattern and stress. 2) Up to four times per day during waking hours, 
subjects will receive random prompts to assess whether they are currently eating or binge eating, as well as 
their stress. With these prompts, we will also be assessing GPS location, to determine medication response on 
these items when subjects are in various ‘food-dense’ environments (e.g., home, restaurant, neighborhood 
density of fast-food restaurants) 3) When subjects start to binge eat, they can initiate smartphone 
assessments assessing eating and stress. Additionally, they will complete an end-of-binge report that also 
assesses eating and stress. 
The cell phone provided to participants will have the app already loaded and ready for use. The data that is 
input will be de-identified because it will be set up with a subject ID. This subject ID will be used to capture 
the data. UMass will not receive a “key” to identify the participants. This application does not qualify under 
the FDA definition as a medical device, and more specifically Software as a medical device (‘FDA Software as a 
Medical Device (SAMD): Clinical Evaluation, Guidance for Industry and Food and Drug Administration Staff, 
issued on December 8, 2017’). Data collected from the app and the Garmin device will allow use to 
understand how stress affects your eating, and how the medication might affect this.
Data Management & Statistical Analysis: The mHealth Core Facility at the University of Massachusetts will 
assist with the collection of electronic data, transmitting and storage of the data, and providing collected and 
processed data to Yale. This data collection system (which integrates the Garmin Band data collection and the 
smartphone data collection) is being developed for the Yale-SCORE (HIC#2000023970; PI, McKee) and 
modified for this project. Statistical support for this project will be provided by biostatistician, Mr. Pittman.
The system involves a smartwatch that participants will wear on their non-dominant hand. The system is 
linked to a smartphone. Participants will be provided with a phone to use for the study duration. Participants 
will wear the system for the first six weeks of the 12-week medication period (3 weeks medication titration + 
3 weeks at full dosing). We believe that this period of time is sufficient to capture medication effects on 
eating behavior. These “real-time” consumption behavior data, along with associated proximal data regarding 
behavior, mood, and stress variables – will be analyzed within subjects over time (to understand dynamic 
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time-varying factors) and between subjects and these data will be linked to the available treatment outcome 
data including follow-ups.
Biosensor Arm:
We will have a separate Biosensor Arm to allow for a wider range of naturalistic eating behavior data 
collection. Participants in the "Biosensor Arm” will wear the Garmin band and interact with the app for a 6-
week period. This 6-week monitoring period can occur at any time (see Biosensor Arm inclusion/exclusion). 
This will provide different insight into stress and eating behaviors and allow data to be collected on a wider 
range of participants. Participants will be provided with the Garmin band (Vivosmart 4), an Android phone 
with the app pre-loaded, and will follow the same procedures as described above (see Procedures for 
Evaluating Naturalistic Eating Behavior and Stress with Wearable Biosensors). The data management and 
statistical analysis will remain through the mHealth Core Facility at the University of Massachusetts as 
described above. The risks, data security & collection, and device information remain the same as the existing 
Biosensor piece.    
The Biosensor Arm is identical to the Biosensor Portion of the main study. It is the same app. 
Participants do not have to be enrolled in the Main Study in order to participate in the Biosensor 
Arm. 
Participants that did not complete the Biosensor as part of the main study while on medication, can 
now participate in the Biosensor Arm if interested. They will sign the Biosensor Consent Form in 
order to participate. Procedures will not be duplicated by any participant. The assessment table 
(Figure 2) lists the assessments completed in the Biosensor.  
Assessments:
Participants will complete baseline assessments prior to starting the 6-week monitoring period. These 
assessments will help to identify possible eating disorder psychopathology and provide baseline information 
for stress and eating behaviors (i.e., EDE-Q/PSS). Participants will then complete the assessments at the end 
of the 6-week monitoring period.
Specific inclusion/exclusion criteria for the biosensor arm are listed in the inclusion/exclusion section of the 
protocol.
  
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Assessments. 
Figure 2. Grid depicting when each assessment is obtained
PRE
DURING TREATMENT
FOLLOW-UP
MEASURE
INSTRUMENT AND REFERENCES
TYPE
BASELINE
LAB #1
WEEK 2
MONTH 1
MONTH 2
MONTH 3
LAB #2
6 MONTH
12 MONTH
BIOSENSOR
Screening Measures
Axis I Disorders
MINI Psychiatric Interview
Interview
*
Binge-Eating Disorder
EDE Interview
Interview
*
*
*
*
BMI
Weight, height
RA Eval
*
*
*
*
*
*
*
*
*
*
*
*
*
Metabolic Measures
Lipids, HbA1c
TSH (as needed)
Blood
*
Safety Measures
Urine screen for pregnancy
Urine drug test for opiates
Urine
*
*
Menstrual Cycle Data
Menstrual cycle calendar, hormone use, 
reproductive and gynecological status
Interview
*
*
*
*
*
*
*
Medical History
Clinical data, incl. start of new treatments 
Interview
*
*
*
Eating Behavior & Food Craving
*
*
*
*
*
*
*
Eating Disorders
EDE-Q
ELOCS
Self-Report
*
*
*
* 
*
*
*
*
*
*
Eating Behavior
TFEQ
YFAS
Self-Report
*
*
*
*
*
Food Craving
Brief Questionnaire of Food Craving
FCI-II
Self-Report
*
*
*
*
*
*
*
*
*
*
*
*
Drive for Palatable Food
PFS 
Control of Eating Questionnaire 
Self-Report
*
*
Hunger
Hunger Ratings
Self-Report
*
*
Health and Behaviors
Depression
Beck Depression Inventory-II
Self-Report
*
*
*
*
*
*
*
Affect
Circumplex Scale
Self-Report
*
*
Perceived Stress Scale
Self-Report
*
Quality of Life
SF-12
Self-Report
*
*
*
Alcohol Use
Audit-2
Self-Report
*
*
*
Physical Activity
Godin Leisure Time Exercise Questionnaire
Self-Report
*
*
*
Sleep
Pittsburgh Sleep Quality Index
Self-Report
*
*
*
Safety & Compliance
*
*
*
*
*
*
*
*
Adverse Events
SAFTEE
Columbia Suicide Severity Rating Scale 
Liver Function
Interview
Blood
*
*
*

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*
Medication Compliance
Pill Counts
Naltrexone and Bupropion levels
RA Count
Plasma
*
*
Vitals
Blood pressure and heart rate
*
*
*
*
*
*
*
*
*
Placebo Rating
Placebo rating by clinician and participant
Self-Report
*
*
Assays
Leptin, ghrelin, estrogen, progesterone
Blood
*
*

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Measures:
Screening Measures

MINI International Neuropsychiatric Interview-Version 7.0 (MINI) [57] is a brief structured interview for 
Axis I psychiatric disorders. Validation and reliability studies have supported the MINI, including good 
convergence with SCID [57]. The MINI requires much less time than the SCID and reduces participant 
burden while providing adequate psychiatric data to characterize patients and determine exclusion 
criteria. 

Eating Disorder Examination Interview–16th Edition (EDE) [58] is an investigator-based interview assesses 
the features of eating disorders and generates eating disorder diagnoses. The EDE will be our primary 
method for assessing binge eating and eating disorder psychopathology. The EDE focuses on the previous 
28 days, except for diagnostic items, which are rated for additional duration stipulations to address DSM-
5 criteria for BED. The EDE assesses the frequency of different forms of overeating, including objective 
binge-eating episodes (OBE; i.e., unusually large amounts of food with loss of control). The EDE also 
comprises four scales (dietary restraint, eating concerns, weight concern, and shape concern) and a 
global severity score. The EDE has good psychometric properties [59], is the major outcome measure for 
BED RCTs [44, 60], and has good test-retest reliability.

Body Mass Index (BMI) will be calculated using measured Height (measured once at baseline) and Weight 
(obtained regularly at assessment meetings). 

Lipid profiles (Lipids): total cholesterol, HDL-, LDL-cholesterol, triglycerides will be obtained fasting per 
established protocols (Anderson et al., 1995). 

Glycemic Control: HbA1c, Glucose and Mean Plasma Glucose, routine measures of average glucose 
control for a previous (3-month) period. 

Hepatic function panel (Liver Function) will be assessed for safety at the first monthly treatment visit and 
at the end of treatment. 

Thyroid-stimulating hormone (TSH) will be assessed if patients report any history of thyroid disease or are 
taking thyroid medications. 

Urine drug testing for opiates will be completed for all participants. 

Urine pregnancy testing will be assessed for female patients of child-bearing potential.

Menstrual Cycle Data: Menstrual cycle calendar (updated regularly), hormone use, reproductive and 
gynecological status

We will also gather sociodemographic information and clinical data on the patient’s medical history and 
comorbidities prior to the study, which we will update as indicated. If patients begin other treatments, 
this will allow us to account for this in analyses.
Eating Behavior & Food Craving

Eating Disorder Examination-Questionnaire Version (EDE-Q). The self-report EDE-Q [61] generates the 
same overeating data and scale scores as the EDE interview. EDE-Q has good test-retest reliability with 
BED patients [59, 62, 63]. The EDE-Q converges well with the EDE as a measure of “change” [64]. 

Eating Loss of Control Scale (ELOCS) [65] assesses the complexity of loss of control eating over the past 
four weeks. The ELOCS has demonstrated good convergent validity and is considered a valid self-report 
questionnaire that may provide important clinical information regarding experiences of LOC in people 
with BED and obesity.

Three Factor Eating Questionnaire (TFEQ) [66] measures eating behaviors with 3 factors: cognitive 
restraint, disinhibition, and hunger. TFEQ has empirical support [67], and shows differential response 
across treatments consistent with putative mechanisms [68, 69]. 
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
Yale Food Addiction Scale (YFAS) [70] is a measure of addictive eating behaviors with high fat/sugar foods. 
Items correspond to the substance dependence diagnostic criteria. The YFAS has demonstrated adequate 
internal reliability, convergent validity, and incremental validity in predicting binge eating.

Brief Questionnaire of Food Craving is a measure food craving we developed based on a 10-item Tiffany 
Questionnaire of Smoking Urges [71] by replacing the word “a cigarette” with “food,” and the word 
“smoke” with “eat.” 

Food Craving Inventory (FCI-II) [72] assesses general and specific food cravings and comprises four 
subscales for different food groups. The FCI has been validated and psychometrically supported in studies 
with obesity and with obesity/BED groups [72, 73]. 

Power of Food Scale (PFS) [74] assesses the psychological impact of and the drive to consume palatable 
foods in an obesogenic environment. The PFS measures appetite for–rather than the consumption of–
palatable foods. The PFS has been validated in large normative (Lowe et al., 2009) and obese samples 
including weight-loss treatment-seeking obese patients [75]. The PFS comprises 3 scales reflecting food 
proximity (food available, food present, and food tasted) supported by factor analysis and good test-
retest reliability and internal consistency (range 0.81-0.91) [75]. The PFS is a good measure of the hedonic 
impact of food environment cues; fMRI studies have reported associations with state cravings for desired 
foods and shifts in brain networks [76]. 

Control of Eating Questionnaire is a single item measure to assess perceived control over eating.

Hunger Ratings is a single item measure 0 to 100 measuring hunger.

Health and Behaviors

Beck Depression Inventory (BDI-II). The BDI [77] is a widely used measure of the symptoms of depression. 
A voluminous literature has documented good internal consistency (studies range .73 to .95), short-term 
test-retest reliability, and convergent validity [78]. 

Circumplex Scale (Circumplex) [79] was modified to a 10-item scale to assess affective state. Participants 
are asked to provide ratings on how they feel right now for each affect item on a scale ranging from 0 
(Not at all) to 100 (Very) on a visual analog scale, and items are classified into positive and negative 
affective dimensions.

Medical Outcomes Study Short-Form Health Survey (SF-12) [80] is widely-used measure of health related 
quality of life. This measure has well-established reliability and validity [81, 82] for physical health and 
mental health domains. 

Godin Leisure Time Exercise Questionnaire (Godin) [83] assesses frequency of mild, moderate, and 
vigorous physical activity. The Godin has good test-retest reliability [83] and has good support from 
validation studies using various activity measurements such as activity monitors and maximum oxygen 
consumption [84].

Pittsburg Sleep Quality Index (PSQI) [85] is a widely used measure of quality and patterns of sleep, 
assessing namely subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleep medication, and daytime dysfunction over the last month. The PSQI has 
demonstrated good internal consistency and reliability (Cronbach’s alpha = .83). 

Alcohol Use Disorders Identification Test (AUDIT-2) [86] is a measure that assesses alcohol use. The AUDIT 
has been used extensively and demonstrates high internal consistency and good test-retest reliability 
[87]. 

Perceived Stress Scale (PSS) [88] is a measure that assesses how much stress an individual is experiencing. 
The PSS has a reliable total score (α=.83), 6-week temporal stability (r=.81) and validity associated with 
health behaviors including eating [89]. 
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Safety and Compliance

Blood Pressure (BP) and Heart Rate (HR). BP readings (both systolic and diastolic) and HR will be obtained 
regularly at assessment meetings.

Systematic Assessment for Treatment Emergent Effects (SAFTEE) [90] Adverse events will be assessed in 
person during study related appointments.

Columbia Suicide Severity Rating Scale (C-SSRS) [91] is a semi-structured assessment intended for 
administration by clinicians or study staff during scheduled study visits. It explores suicidal ideation and 
intensity, as well as behaviors and lethality.

Pill Counts. Participants will be asked to bring their medication to their last appointment and clinicians will 
count and record the number of pills remaining.

Naltrexone and Bupropion levels plasma will be collected at weeks 4 and 12 to evaluate plasma trough 
levels of bupropion, naltrexone, 6-beta-naltrexol levels. 
Assays

Assays will be processed by the Core Laboratory at the Yale Center for Clinical Investigation. These include 
leptin, ghrelin (octanoylated and des-octanoylated), and estrogen/progesterone. Samples will be stored 
in -70 freezer, and batched for processing. Medication levels will be processed and stored in a -70 freezer 
until sent to World Wide Clinical Trials for analysis.
Assessment Training: Independent outcomes assessors will be trained in the study interviews by investigators 
following well-established protocols from previous grants. Once interviewers are certified in the measures they 
will receive ongoing supervision to ensure consistent use and prevent drift. Dr. Grilo will do inter-rater reliability 
studies, as before for BED (Grilo et al., 2004) and psychiatry (Zanarini et al., 2000). 
Maintenance of Cohort. Research staff will form on-going relationships and maintain contact with participants. 
Our experience indicates this improves likelihood of participants’ willingness to perform follow-up assessments. In 
addition: (1) At pre-screening and baseline assessment, participants will be asked whether they will be available 
for the entire study duration; (2) Participants will be excluded if unable to comply with birth control methods; (3) 
Participants will provide names and contact information of at least two relatives or friends and permission to 
contact them if they move without notifying investigators; (4) At each assessment, participants will be asked if 
they have plans to move; and (5) We will reimburse participants for completion of the assessments.
5.
Genetic Testing   
N/A ☒
6.
Subject Population: Provide a detailed description of the types of human subjects who will be recruited into 
this study.
Two hundred (N=200) participants with BED with and without obesity (n=100 and n=100, respectively), and 
meeting other eligibility criteria as described below, will be randomized to participate in this trial. Previous 
work with this population suggests participants will be adults, male and female, and represent diverse 
racial/ethnic and sociodemographic groups.
7. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled 
in the study? If so, identify the population of subjects requiring special safeguards and provide a justification 
for their involvement.
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☐Children
☐ Healthy 
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☐ Females of childbearing potential
☒N/A
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐  No ☒ 
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion Criteria:
(1) 18 to 70 years old;
(2)
Meet DSM-5 criteria for BED based on semi-structured diagnostic interview (EDE);
(3)
BMI in the obesity (BMI >30 and <50) or non-obesity (BMI >21.5 and <29.9) range; 
(4)
Available for the duration of the treatment and follow-up (15 months).
(5)
Read, comprehend, and write English at a sufficient level to complete study-related materials.
(6)
Provide a signed and dated written informed consent prior to study participation.
Exclusion criteria: 
Main exclusion criteria reflect primarily clinical or medical issues that would indicate different treatment 
needs or contraindication to NB medication. 
(1) Predisposition to seizures (e.g., history or evidence of seizure disorder, febrile seizures during childhood, 
brain tumor, cerebrovascular disease, or significant head trauma; family history of idiopathic seizure 
disorder, or is currently being treated with medications or treatment regimens that lower seizure 
threshold).
(2)
Lifetime anorexia or bulimia nervosa, or currently regularly self-inducing vomiting.
(3)
Co-existing psychiatric condition that requires hospitalization or more intensive treatment (e.g., bipolar 
mood disorders, psychotic illnesses, severe depression).
(4)
Currently taking a medication that is a contraindication to NB medication (MAOI, opiates, 
benzodiazepines, CYP2B6 inhibitors, bupropion, naltrexone).
(5)
Positive urine drug screen for opiates.
(6)
History of allergy or sensitivity to bupropion or naltrexone.
(7)
Serious uncontrolled medical conditions (including renal or hepatic impairment, neurological, chronic 
pulmonary disease, or any other serious, unstable medical disorder).
(8)
Breast-feeding or pregnant. 
(9)
Uncontrolled hypertension with a seated systolic blood pressure > 160 mmHg, diastolic blood pressure 
> 100 mmHg, or heart rate > 100 beats/minute.
(10)
Previous surgical or device intervention for obesity within the past 5 years.
(11)
Have not donated blood for 6 weeks prior to the study and agree not to donate blood for 8 weeks 
following their participation.
(12)
History of congenital heart disease, cardiovascular disease, cardiac arrhythmias requiring medication, 
atherosclerotic disease, or a history of cerebrovascular pathology including stroke.
(13)
Current uncontrolled Type I or Type II diabetes mellitus.
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(14)
Untreated hypothyroidism with a TSH > 1.5 times the upper limit of normal for the test laboratory with 
repeat value that also exceeds this limit.
(15)
Untreated gallbladder disease.
(16)
Current or recent (within 12 months) drug or alcohol dependence 
(17)
Currently receiving effective treatment for eating or weight loss. 
(18)
Currently participating in another clinical study in which the participant is or will be exposed to an 
investigational or a non-investigational drug or device.
(19)
Reports active suicidal or homicidal ideation. 
Biosensor Arm:
Inclusion Criteria:
(1)
18 to 70 years old.
(2)
Willing to wear the Garmin band and interact with the app daily for 6 weeks.
(3)
Read, comprehend, and write English at a sufficient level to complete study-related materials.
(4)
Provide a signed and dated written informed consent prior to study participation.
Exclusion criteria: 
(1)
Co-existing psychiatric condition that requires hospitalization or more intensive treatment (e.g., bipolar 
mood disorders, psychotic illnesses, severe depression).
(2)
Serious uncontrolled medical conditions (including renal or hepatic impairment, neurological, chronic 
pulmonary disease, or any other serious, unstable medical disorder).
(3)
Breast-feeding or pregnant. 
(4)
Previous surgical or device intervention for obesity within the past 5 years.
(5)
Currently receiving effective treatment for eating or weight loss. 
(6)
Current uncontrolled medical condition or medication that could impact weight or eating behavior.
(7)
Currently participating in another clinical study in which the participant is or will be exposed to an 
investigational or a non-investigational drug or device.
(8)
Reports active suicidal or homicidal ideation.
9. How will eligibility be determined, and by whom? Write here
Participants will be interviewed by a trained research clinician (MINI and EDE) to determine whether they 
meet criteria for binge-eating disorder. These diagnostic clinical interviews will also determine whether 
participants have any co-existing psychiatric conditions (including substance use disorders) that require 
hospitalization or more intensive/different treatment.
The study physician will determine medical eligibility based on results of participants’ physical examination 
(within one year of starting the study), as well as results of the baseline assessment and blood/urine testing. 
Information obtained from the physical examination will include a list of current medications, which 
participants will be asked to bring to their baseline assessment.
Biosensor Arm: Eligibility is determined by trained research clinicians. Physical exam and blood/urine testing 
are not required since the Biosensor is non-invasive and there is no medication administered.
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
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NB Pharmacotherapy. 
Since participants will undergo a thorough physical evaluation and screening for known contraindications for 
treatment with the NB medication, potential risks will be minimized. In clinical trials, NB was associated with 
the following side effects in 10% or more of the time and significantly greater than rate in placebo: nausea, 
headache, constipation, and vomiting. NB was associated with the following side effects less than 10% of 
cases but significantly more than placebo: dizziness, insomnia, dry mouth, and diarrhea. Large studies (e.g., 
Greenway et al., 2010 with N=1742) reported that the proportion of participants reporting a serious adverse 
event did not differ between NB and placebo (1.6% versus 1.4%) and that none of the observed events were 
judged to be related to the study. It appears important to evaluate and monitor blood pressure and heart rate 
because studies have found that patients with obesity treated with NB have significantly lower drops than 
placebo in systolic BP changes (-0.4 vs. -2.1), diastolic BP (-0.1 vs -1.0), pulse rate (1.0 vs -0.1) (Greenway et 
al., 2010). 
Pill Placebo. 
The main risk associated with placebo is failure to improve, although some persons do improve solely on 
placebo. Although the placebo is inactive, some persons who take the placebo report that they experience 
some of the side-effects listed above. 
Assessments and Interviews. 
Participation of the human laboratory component does not add risk above that associated with the clinical 
trial, with the exception of repeated blood drawing. Risks will be minimized by using trained research nurses. 
Further, subjects have not donated blood for 6 weeks prior to the study, and they are informed to not donate 
blood for 8 weeks following their participation.
Participation in the biosensor component does not add risk. De-identified biosensor and smartphone data will 
be remotely collected by mHealth Core Facility at UMass for data processing. 
Research assessments are all noninvasive, and add no substantial risk. The major disadvantages are the time 
taken to complete them and possible breach of confidentiality. Our past experience with these measures 
indicates that they are acceptable to participants. Careful efforts aimed at maintaining confidentiality will be 
made. All identifiable information will be stored in a locked research cabinet. All participants will be assigned 
a study participant number.  A list of numbers and the corresponding names will be maintained by the 
Principal Investigator and stored in a locked research cabinet. Any identifying information that is collected will 
be kept in a locked research cabinet in a locked unit. Any information published as a result of the study will be 
such that it will not permit identification of any participant. All information collected will remain confidential 
except when we are legally required to disclose such information by law. These circumstances include 
knowledge of abuse of a child or elderly person, threats of harm to self or others, and plans to harm to 
property. Data will be stored in locked cabinets for 7 years after the final data are collected. Research records 
may be the subject of an audit by a regulatory agency within the federal government. Organizations which 
have a responsibility for protecting human subjects, including the Yale IRB (Human Investigation Committee), 
may have access to the research records. Additionally, the funding agency (NIH) may have access to the 
research records. The participant’s identity will remain protected except as required for legal or regulatory 
inquiries. Individually identifiable health information will be protected in accordance with the Health 
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Insurance Portability and Accountability Act of 1996. All research personnel will be trained on IRB, ethics, and 
HIPAA procedures.
There is the possibility that drawing blood might cause a small bruise, mild discomfort, or infection.
Failure to Improve. 
There is a chance that the patient's binge eating or obesity may fail to improve or may worsen during the 
study.
Biosensor- Physical Discomfort from Wristband.
As part of the study, subjects will wear a Garmin wristband and carry a smartphone for the collection of data. 
While there is potential physical discomfort associated with regular wearing of a wristband, our experience 
suggests that this has been minimal and subjects have been comfortable wearing the device for extended 
periods of time. The wristband is adjustable. 
Biosensor – Android Cell Phone App
All information collected from both the Garmin wristband and the Android cell phone app will be de-
identified. The data from the bands in continuously transmitted o the mHealth Core Facility at UMass through 
the Garmin service for Academic Researchers. The data from the Android cell phone app will be collected, 
transmitted, and stored by the mHealth Core Facility at UMass and provided to Yale.
Data Security and Collection. 
Security of user information is of paramount importance to us. We have completed a Security Design Review 
(INC1917498) through Yale ITS and have received approval using this technology (HIC# 2000023970, 
McKee[PI]). Security of user information is of paramount importance to us.  We work to protect security of 
sensitive information during transmission by using Secure Socket Layer (SSL) software, which encrypts 
information that is input.  Our servers are behind a firewall, and we secure it using the best available 
methods.  This data will not be associated with any personal information of the participant; rather, it will only 
be associated with a random key associated with the phone.  The study organizers at Yale will keep a mapping 
between the random key and the identity of the individual. We will include privacy safeguards to ensure that 
participants are comfortable with the data they are revealing. The user will be asked to specify privacy zones 
where they do not with GPS information to be recorded. This can be done at any point during the study by 
contacting study organizers or they can explicitly turn on or off GPS logging by using the Settings screen on 
the app. During periods when location logging is enabled, the system will automatically upload location data 
to a secure backend database.  
We note that Dr. Ganesan has recently completed an NIH R01 (DA033733-01) where we monitored cocaine 
addicts in out-patient settings with several on-body sensors (wristband, chestband, and smartphone), which 
had even more extensive data collection than we are proposing in this grant (we collected GPS, respiration, 
ECG, phone usage patterns, and other signals in the R01 effort). They are also part of several other efforts 
with similar data collection considerations (NSF 0910706 and NIH 1-U54EB020404-01). Hence, we have 
extensive experience in mitigating the potential risks, and privacy issues associated with the collection of, and 
use of sensitive on-body sensor data. Given our experience in this domain, we will follow all the best practices 
in acquisition and management of subjects’ private data.
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11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
Effective screening will exclude all prospective participants who would be at greater risk for complications 
because of medical or psychiatric illnesses. Subjects will be evaluated repeatedly throughout the study and 
will be monitored for any adverse reactions. Given the uncertain effects of medication during pregnancy, the 
following precautions will be taken for women of reproductive age: 1) a female participant of reproductive 
age must agree to use a reliable method of birth control while she is in the study and to alert the research 
team if she departs from her birth control plans or if, in spite of adherence to these plans, she thinks she 
might be pregnant; we will do a urine pregnancy test as needed during the treatment phase of the study, and 
2) if a woman becomes pregnant after study entry, her medication will be discontinued.  
Screening for opiate use and warning about opioid withdrawal. During the screening process, we will conduct 
urine drug screens for opiate use as part of the medical evaluation if patients report a lifetime history of 
substance use disorder with opiates, or if patients report any use of opioid-based pain medications within the 
past 6 months. Additionally, we will include this advisory pertaining to opioid use and examples of opioid-
based medications and drugs in the written consent form as well as the verbal consent process: Naltrexone 
can cause withdrawal symptoms in individuals who are taking opioid pain medications or drugs. You should 
not participate and we will not include you in the study if we know or suspect you are using opiate-containing 
drugs.
Monitoring weight loss. Participants who have a BMI in the healthy-weight or overweight range (i.e., BMI 
21.5-29.9 kg/m2) will be monitored closely for changes in weight. If any participant’s weight drops below 20.0 
kg/m2 over the course of the study, this will trigger a discussion amongst investigators and the study 
physician. Research clinicians will review and/or assess eating behaviors to ensure the patient is not vomiting. 
This will be discussed with the team along with any reported side effects, and whether the treatment should 
continue per protocol, dosage decreased, or medication stopped will be considered. We anticipate this will be 
a rare occurrence; however, the use of this “early signal” (i.e., weight below 20.0 kg/m2) will greatly reduce 
the likelihood of adverse events.
Monitoring depressive symptoms. Depressive symptoms will be monitored frequently. To monitor changes in 
depressive symptoms, patients will be asked to complete the BDI-II at all clinic visits (2x in first month, 
monthly thereafter). Research clinicians will review BDIs during the clinic visit, and will asked pointed 
questions pertaining to suicidality/suicidal ideation using the Columbia Suicide Severity Rating Scale. If it 
appears, based on the clinical judgment of the research clinician, that the participant is experiencing 
significant adverse effects of the medication, the investigators and study physician will be consulted and a 
determination of whether to discontinue the medication will be made. The participant will be compensated in 
full, and will be asked to continue to attend clinic visits and to continue to participate (if applicable) with the 
behavioral support to ensure remission of any distressing symptoms. If warranted, the participant will be 
given a referral. There is no assessment of suicidality in the Biosensor Arm. 
Blood pressure and heart rate will be measured during all evaluation visits. Two readings will be taken at each 
assessment. In the event of systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥ 100 mm 
Hg, or an increase in heart rate of ≥15 bpm (from baseline), the study physician will be notified and will 
determine whether additional intervention and/or medication discontinuation is warranted. 
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Liver function will be measured during baseline, at month-1 clinic visits, and at the end of treatment. The 
study physician will review results of a full hepatic panel prior to the start of treatment and throughout 
treatment. Participants with hepatic disease will be excluded if this is detected at baseline, per exclusion 
criteria. Any changes and out-of-range values will be flagged immediately by research clinicians, and the study 
physician will determine whether additional intervention and/or medication discontinuation is warranted.
Wallet Safety Card. Each participant will be given a wallet card with the code number for the medication 
assignment in the event of an emergency and the need for breaking the blind. The research pharmacy has 24-
hour service. Participants will be provided with contact information for the study physician and the PI, as well 
as emergency numbers in case of adverse events or other concerns. Research staff will have cell phones and 
can be reached 24/7.
Medication Titration & Taper. 
Participants will have four weeks of up-titration: one tablet daily (Naltrexone 8mg/ Bupropion 90mg; 1 week), 
then two tablets daily (Naltrexone 16mg/ Bupropion 180mg; 1 week), then three tablets daily (Naltrexone 
24mg/ Bupropion 270mg; 1 week), to reach the full dose of four tablets daily (Naltrexone 32mg/ Bupropion 
360mg). 
If participants drop out of the study during, we will ask that they return any unused medication. Participants 
who have been on the study medication for more than 4 weeks, including those who complete the treatment, 
will be asked to taper off the study medication: two tablets daily (Naltrexone 16mg/ Bupropion 180mg; 4 
days), then one tablet daily (Naltrexone 8mg/ Bupropion 90mg; 3 days), to discontinue medications. 
Participants on placebo will take the same number of tablets as the active group to maintain the blind. 
Participants will be cautioned against stopping the medication abruptly. Taper off is not medically necessary 
for participants on the study medication for 4 weeks or less.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Greater than minimal.
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? n/a
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety-
monitoring-plans-templates for
i.
Minimal risk
ii.
Greater than minimal
The principal investigators will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews semi-annually.  Although this study qualifies as clinical trial research, it does not 
meet NIH criteria for Phase III clinical trial research. Nonetheless, this study will be monitored semi-annually 
by a Data Safety Monitoring Board (DSMB) as the study involves a double-blind placebo controlled evaluation 
of medication effects that may involve greater than minimal risk. Adequate surveillance and protections will 
be put in place to discover adverse events promptly and keep their effects to a minimum. 
During the review process, the principal investigators and DSMB will evaluate whether the study should 
continue unchanged, require modification/amendment, or close to enrollment. Either the principal 
investigator, the IRB or the DSMB have the authority to stop or suspend the study or require modifications.
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The risks associated with the current study are deemed greater than minimal for the following reasons: 
1.
We do not view the risks associated with the NB combination medication as minimal risks.
2.
Given the now established safety and validity of the current NB combination medication in RCTs and 
FDA approval, we do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to 
predict with certainty the absolute risk in any given individual. Therefore, we provide a plan for monitoring 
the data and safety of the proposed study as follows:
DATA AND SAFETY MONITORING PLAN 
The treatment interventions and assessment protocols are well-established and pose primarily low risks to 
subjects. The DSMP focuses on close monitoring by the PIs in conjunction with the study MDs. Excessive 
adverse events and/or any serious events (should they occur) will be reported promptly to the NIH and to the 
Yale Human Investigation Committee.  
A Data and Safety Monitoring Board (DSMB) will monitor this project. The DSMB is composed of Yale 
investigators who are independent of the proposed trial and experienced in various aspects relevant to the 
current proposal including: conduct of clinical trials, biostatistics, primary care, and the clinical management 
of obesity and BED. 
We have developed a standard DSMB report form that summarizes, on a semi-annual basis:
1.
Recruitment, retention, and follow-up rates for the study and compares them to target rates.
2.
Rates of data completeness and availability of primary outcome data
3.
Occurrence of AEs and SAEs
4.
Report of study progress since the last report.  
5.
Rates of recruitment of women and minorities with respect to targets.
These reports are generated by the study coordinator, signed by each study PI prior to their submission to the 
DSMB. DSMB comments are documented and forwarded to the Yale IRB at the time of the annual review and 
reapproval. They will also be summarized as part of the annual progress report to NIDDK. However, if adverse 
events occur in greater magnitude or frequency than expected these will be reported to the DSMB, HIC, and 
NIH prior to scheduled reports. The Principal Investigators (Grilo & McKee) will assume full responsibility for 
reporting serious and non-serious and unanticipated adverse events. The DSMB may call an ad-hoc meeting 
to address emergent safety concerns.
Because the projected effect sizes may not be large enough for detection during interim analyses, we are not 
proposing a preliminary analysis of accumulating efficacy and safety data by treatment assignment. Instead, 
we propose to submit semi-annual reports of aggregate data to the DSMB members that contains screening 
data, baseline demographics, retention data, serious adverse events data, as well as accrual status including 
projections, times to milestones, and any other data that will help in the assessment of the clinical trial. Based 
on this report, each DSMB member will complete a form making one of two recommendations: 1) continue 
recruitment as planned; or 2) schedule formal DSMB meeting immediately. If any DSMB member 
recommends a meeting, this will be scheduled within one week, minutes will be kept, the report will be 
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reviewed with the PI, and the committee will vote on whether the study should: 1) continue recruitment 
unchanged; 2) continue with a protocol amendment; 3) stop recruiting pending further investigation. If, after 
this meeting, any DSMB member votes to stop recruitment or requests a protocol modification, the Yale IRB 
will be informed.
Measurement and reporting of adverse events. 
Adverse event data will be collected on an on-going basis. These data will be collected and examined with 
blindness to the medication condition (Naltrexone/Bupropion or placebo). Adverse events data will be 
reviewed by the PI, co-investigators, and the DSMB throughout this trial (see Table below). A summary of 
adverse events will be provided to the Yale IRB yearly during the annual renewal review process. Any serious 
or unanticipated adverse events will be reported to the NIH and to the Yale IRB within 48 hours.   
The frequency of data review is summarized in the following table: 
Table
Data type
Frequency of Review by 
PIs and Research Team
Frequency of  Review 
by PI and DSMB
Table 1
Subject accrual 
Monthly
Twice-yearly
Table 2
Treatment completion rates (retention/attrition)
Twice-yearly
Twice-yearly
Table 3
Adverse and serious adverse event rates
Twice-yearly
Twice-yearly
Table 4
Checklist for DSMB
NA
Twice-yearly
Attribution of Adverse Events:  
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures by the investigators according to the following categories:
a)
Definite: Adverse event is clearly related to the investigational procedure/agent.
b)
Probable: Adverse event is likely related to the investigational procedure/agent.
c)
Possible: Adverse event may be related to the investigational procedure/agent.
d)
Unlikely: Adverse event is likely not to be related to the investigational procedure/agent.
e)
Unrelated: Adverse event is clearly not related to the procedure/investigational agent.
Plan for Grading Adverse Events:  
The following scale will be used in grading the severity of adverse events noted during the study:
1.
Mild adverse event
2.
Moderate adverse event
3.
Severe adverse event
Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events: In addition to grading the adverse event, the PI will determine whether the 
adverse event meets the criteria for a Serious Adverse Event (SAE).  An adverse event is considered 
serious if it results in any of the following outcomes:
1.
Death;
2.
A life-threatening experience in-patient hospitalization or prolongation of existing hospitalization; 
3.
A persistent or significant disability or incapacity; 
4.
A congenital anomaly or birth defect; OR
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5.
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition.
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event.  
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE.  It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
Plan for events to the Yale IRB that are unexpected AND related AND involve risk of harm to subjects or 
others:
The PIs will report any incident, experience, or outcome that meets all three of these conditions to the IRB 
immediately: 
1.
Unexpected (in nature, specificity, severity, or frequency); given (a) the research procedures 
described in the protocol-related documents, such as the IRB-approved protocol and informed 
consent document and (b) the characteristics of the subject population being studied; AND
2.
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND 
3.
Suggests that the research places participants or others at greater risk of harm (physical, 
psychological, economic, legal, or social) than previously known or recognized. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non-medical in 
nature, and include – but are not limited to – serious, unexpected, and related adverse events and 
unanticipated adverse device effects.  Adverse events are reportable to the IRB as UPIRSOs only if they 
meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the appropriate 
forms found on the website. All related events involving risk but not meeting the prompt reporting 
requirements described in IRB Policy 710 should be reported to the IRB in summary form at the time of 
continuing review and/or a current DSMB report. If appropriate, such summary may be a simple brief 
statement that events have occurred at the expected frequency and level of severity as previously 
documented.  
Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s research 
monitors, e.g., study sponsors, funding and regulatory agencies, and regulatory and decision-making bodies: 
For the current study, the following individuals, funding, and/or regulatory agencies will be notified: 
i. All Co-Investigators listed on the protocol 
ii. National Institutes of Health 
The investigators will conduct a review of all adverse events upon completion of every study subject. The 
investigators will evaluate the frequency and severity of the adverse events and determine if modifications to 
the protocol or consent form are required.
Procedures for providing follow up care:
Medical monitoring will occur at all clinic and follow up visits and medical care will be provided if warranted. If 
a study participant experiences any psychiatric symptoms or distress (e.g., depressive symptoms or 
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suicidality) at any stage of study participation he/she will receive short-term treatment and support from the 
study treatment team (including psychologists and a psychiatrist) and will be connected to a local emergency 
department (e.g., the Crisis Intervention Unit at Yale-New Haven Hospital) and his/her physician or therapist 
for ongoing care.
Measurement and reporting of subject accrual, adherence to inclusion/exclusion criteria. 
Review of the rate of subject accrual and adherence to inclusion/exclusion criteria will occur regularly by the 
PI and co-Investigators and yearly by the DSMB. These reviews will help to assure that participants meet 
eligibility criteria and ethnic diversity goals outlined in the grant proposal. 
Measurement and reporting of participant treatment completion rates. 
Participation rates (retention and attrition) will be reviewed on an ongoing basis by the PIs and co-
investigators to identify any potential problems, and formally by the PIs and DSMB semi-annually.  Any 
differential dropout across blinded study groups and/or higher than expected dropout will be reviewed by the 
investigators to determine whether any problems are present and what, if any, corrective action needs to be 
taken.
During the reviews, if the DSMB has concerns about whether attrition has reached a level that might inhibit 
the ability of the study to address its primary aims, they will suggest a meeting to discuss methods for 
improving subject retention. Previous pharmacotherapy studies for BED (with comparable time frames for 
pharmacotherapy) have reported attrition rates between 20% and 38%.  Studies of bupropion for obesity 
treatment reported attrition of 30% to 38%. Thus, “trigger points” for review and discussion by principal 
investigator and research staff will be:  35% (“low alert”), 40% (“mid alert”), 45% (“high alert”), 50% 
(“extreme alert”).  With early alerts to problems, action would be taken to avoid higher level alerts; if a 
higher-level alert should arise, more drastic actions would be taken.  
The following actions would be taken at each level of alert: 
(1) Low-level alert = Review of potential problems by PI.
(2) Mid-level alert = Meeting with co-investigators to discuss approaches to minimize further losses to 
follow-up/dropouts. 
(3) High-level alert = Meeting with co-investigators to determine further alterations of study protocol to 
complete the study with no further losses.
(4) Extreme-level alert = In the unlikely event of a 50% dropout rate prior to the mid-study time point, 
discontinuing the trial would be considered.
Trial Stopping Rules
Given that this study is deemed greater than minimal risk to human subjects but not high risk, it is more likely 
that attrition or difficulty in recruiting adequate numbers of participants will require stopping the trial than 
would excess adverse events.  However, as outlined, adverse events will be monitored in all participants, and 
the DSMB, together with the PI, will alert the Yale IRB and the NIH if a larger (or more serious) than 
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reasonably expected adverse event rate should occur.  Other potential issues relating to stopping rules for 
this trial include: 
1.  New Information 
It is unlikely that any new information will become available during this trial that would necessitate 
stopping the trial.  If new safety data (i.e., pertaining to short-term use of the study medication) become 
available, this will be evaluated. 
2.  Limits of Assumptions 
It is possible that baseline differences between the treatment conditions, excessive attrition, and/or 
missing data could limit the value of data analysis. Baseline differences across blinded treatment groups, 
if present, will be evaluated yearly and considered in relation to potential effects on the power to detect 
differences in the primary outcomes.  If these effects were to develop and be sizeable, alterations to the 
randomization schedule would be considered. Any plans to alter the randomization scheme would be 
communicated to the NIH. 
3.  Limits of Rules 
There are other situations that could occur that might warrant stopping the trial and/or including a 
section on the safety report entitled “Other situations that have occurred since the last safety report that 
warrant discussion” to allow for communication of concerns. 
Finally, as currently outlined above, the DSMB has the authority to stop the trial following any serious adverse 
event or following any semi-annual review of adverse events. 
13. Statistical Considerations: Describe the statistical analyses that support the study design. 
Baseline demographic and clinical characteristics for the randomized groups will be compared using chi-
square tests for categorical variables, and ANOVA or Kruskal-Wallis tests for continuous variables. Continuous 
variables will be examined for normality using normal probability plots and Kolmogorov-Smirnov test 
statistics. If normality is not satisfied, transformations or nonparametric alternatives will be considered. 
Dropouts and completers will also be compared. Primary analyses will be based on an intent-to-treat basis. 
Primary outcomes will be tested at the two-sided alpha 0.05 threshold. Secondary analyses will be adjusted 
for multiple tests using the Bonferroni correction basing the adjustment on the number of conceptually 
related statistical tests within each hypothesis.
Overall analysis strategy. Mixed-effects models [92] will be used to compare treatments. These models allow 
for different numbers of observations per subject, use all available data on each subject, and are unaffected 
by randomly missing data. A further advantage is the capacity to test and account for individual-difference 
contributions to the treatment outcomes (Cudeck, 1996; Cudeck & Klebe, 2002; Hedeker et al., 1996; 
Hedeker & Gibbons, 1996; Singer, 1998). They provide flexibility in modeling the correlation structure of the 
data. In models for each outcome in Aims 1 & 2, we will include obesity status (obese vs. non-obese) and 
treatment (NB vs. placebo) as between-subject effects, time (see Aim-specific study time points) as a within-
subjects factor, and subject as the clustering factor. Across analysis, time-points associated with the 12-week 
treatment phase will be considered as primary outcomes, and all analyses will be repeated to examine change 
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during the 12-month follow-up period. All possible interactions will be modeled and the following primary a 
priori contrast will be tested: 1) placebo NB vs. active NB. Least-square means will be plotted and compared 
post-hoc to interpret significant effects. Because we cannot a priori predict the shape of the response over 
time in each arm of the trial we will first treat time as a categorical predictor and will then test for polynomial 
trends over time. We will consider different error structures (e.g., AR1, CS, independence) and select the best 
fitting one based on Schwartz’ Bayesian Criterion (BIC). We will compare dropout patterns between groups 
and if there are concerns of informative dropout or informative intermittent missing data, we will use pattern 
mixture models [93] to perform sensitivity analyses. Secondary models will include subjects with complete 
data. To test for assessment reactivity, we will evaluate whether biosensor assessment (yes/no; between-
subject variable) moderates our primary outcomes in Aim 1 (as either a main effect, or interacting with 
medication). If this is found, then all subsequent analyses for Aims 1 & 2 will be limited to the sample (n=140) 
without the biosensor assessment.
Primary Aim 1. We will use the mixed models described above to test the effectiveness of NB medication for 
BED patients with and without obesity. The primary aims are to evaluate NB medication for (a) reducing binge 
eating frequency; and (b) in the patients with obesity, for reducing % weight loss. Significant NB main effects 
(regardless of obesity status) on frequency of binge eating will be considered supportive of our primary 
hypothesis. We also expect that NB will be associated with significantly greater reductions in % weight loss 
among the BED+obese group. In view of the factorial design, we will also be able to assess whether obesity 
status moderates reductions in binge eating frequency. These analyses will focus on 12-week outcomes. 
Secondary analysis will be repeated to examine change during the 12-month FU period.
Secondary Aims. (a) Explore effectiveness of NB medication for BED patients with and without obesity on 
secondary outcomes: eating-disorder pathology (EDE global), eating behaviors (EDE, TFEQ, FCI, PFS), 
depression (BDI-II), psychosocial functioning (SF-36), metabolic measures (lipid profiles, HbA1c, blood 
pressure, heart rate) and “remission” and “relapse” from binge eating behaviors. The continuous secondary 
outcomes (e.g., EDE global, BDI-II, SF-36) will be analyzed using the same approach as for primary aim 1, and 
logistic regression will be used to compare proportion achieving remission from binge eating or relapse to 
binge eating. (b) Explore predictors, moderators, and mediators of primary outcomes (i.e., binge eating).  In 
terms of treatment processes, we will attempt to replicate our findings regarding the prognostic significance 
of rapid response for behavioral and pharmacologic treatments (Grilo et al., 2006, 2012, 2015; Masheb & 
Grilo, 2008). We will follow Kraemer’s (2002) conceptual/statistical models for exploring predictors, 
moderators and mediators for binge eating. Per Grilo et al. (2012), we hypothesize that overvaluation of 
shape/weight and depression levels to be significant predictors; such findings would inform future treatment 
prescription regarding this pharmacologic intervention. Per Kraemer (2002), we will explore if baseline 
characteristics predict/moderate treatment effects by testing for main effects and interactions in models 
specified above for primary outcomes. In terms of mediators, we will explore whether differential symptom 
changes during treatment are associated with subsequent longer-term primary outcomes. Repeated 
assessments of eating behaviors (EDEQ and TFEQ scales), and food-reward constructs (FCI, PFS) relevant to 
putative mechanisms of action for NB, will yield relevant change variables for analyses of mediation (i.e. 
testing subsequent changes in binge eating).
Primary Aim 2. To evaluate potential mechanisms underlying the effect of NB on binge eating behavior, we 
will first evaluate whether NB treatment changes latency to resist eating, calories consumed, leptin, ghrelin, 
and food craving employing the mixed models described above. If a potential mechanism demonstrates a 
significant time x medication effect, we will then evaluate whether improvement in the variable of interest 
mediates changes in frequency of binge eating over the 12-week treatment period. Following the general 
analytic framework outlined by Kraemer (2002), we will use the product of the coefficients method to 
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evaluate the relationship between the mediator, or indirect effect, and outcome. After running a regression 
equation to determine (1) the effect of treatment on the mediator (provides beta weight for a), we will 
evaluate (2) the strength of the relationship between the mediator, treatment, and outcome (provides beta 
b). Using MacKinnon’s software PRODCLIN, we will evaluate the asymmetric confidence intervals for the 
product of the regression estimates (a*b). Importantly, we note that statistical mediation is not equivalent to 
causation, and will be sure to appropriately limit our conclusions. Significant NB main effects in latency to 
resist eating, calories consumed, leptin, ghrelin, and food craving will be considered supportive of our 
hypothesis. Further, significant mediation of NB-related changes in lab variables on clinical outcomes 
(reduction in binge eating frequency) will be considered supportive of our hypothesis.
Exploratory Aim 3. To account for the hierarchical structure of the data, linear mixed models will be used to 
assess differences over time in affect and eating behaviors per day collected over a 6-week period. To 
evaluate potential mechanisms underlying triggers of binge eating behavior, we will first evaluate whether NB 
treatment changes eating behavior. We will also evaluate the time course of affect and eating behaviors to 
identify potential antecedents and consequences of binge eating episodes.
Supplementary analysis: Retention, compliance, and sex. These analyses will provide insight into outcomes 
which will help us to consider directions for future research. We plan to explore whether medication 
compliance [plasma bupropion, naltrexone, 6-beta-naltrexol levels, pill counts], and length of time in 
treatment influenced our primary outcomes. Analyses described earlier will be repeated separately with a) 
counts of pills taken as a covariate, and b) length of time in treatment as a covariate. In participants taking 
active medication we will conduct a logistic regression examining area under the curve for the three plasma 
medication levels as a predictor of our primary outcome (frequency of binge eating) and as predictor of 
treatment-related change in potential mechanisms. Associations between plamsa medication levels and 
changes in mechanisms will provide an indication that medication is driving the change in the predictor 
variable. We also plan to evaluate whether sex moderates medication effects on all study outcomes. Analyses 
described in D.7.3. will be repeated with sex as between subject variable. We will also explore effects related 
to laboratory outcomes assessing estrogen and progesterone levels as covariates.
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SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
A.  RADIOTRACERS
☒N/A
B.  DRUGS/BIOLOGICS    ☐N/A
1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the category that 
applies (and delete the inapplicable categories):
Exempt Category 1: The clinical investigation of a drug product that is lawfully marketed in the United States 
can be exempt from IND regulations if all of the following are yes: 
1.
The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug.
☒
2.
The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product.
☒
3.
The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product
☒
2.
The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 
21 CFR Part 56).
☒
3.
The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
☒
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 Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
☐i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
☐ Blood grouping serum
☐ Reagent red blood cells 
☐ Anti-human globulin
☐ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
☐iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
 Exempt Category 3
☐ The drug is intended solely for tests in vitro or in laboratory research animals if shipped in accordance with 
21 CFR 312.60
 Exempt Category 4 
☐ A clinical investigation involving use of a placebo if the investigation does not otherwise require submission 
of an IND. 
2. Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the 
first time this drug is being administered to humans, include relevant data on animal models. 
In September 2014, the FDA approved (“Contrave”) the combination of naltrexone and bupropion to treat 
obesity consisting of the following empirical support from several RCTs performed with obesity (but not BED). 
NB medication will combine naltrexone sustained-release (SR, 32 mg/day) combined with bupropion SR (360 
mg/day) taken daily (8 mg naltrexone/90 mg bupropion in each tablet – two tablets taken twice daily; 
matching tablets and frequency for placebo).
Mechanisms of Action. The putative mechanisms of action for NB seem relevant for binge eating in addition 
to weight loss. Naltrexone, an opioid receptor antagonist, is approved to treat alcohol and opioid dependence 
[94]. Naltrexone produces weight loss in lab animals but only minimal weight losses in people [95, 96]. 
Bupropion operates through dopaminergic, noradrenergic, and nicotinic acetyl-cholinergic mechanisms [51-
53]. Bupropion may target reward processes that drive eating behaviors, consistent with its FDA indication for 
treating nicotine dependence and reduced weight gain during smoking cessation [54, 55]. Bupropion 
promotes weight loss [56]: in a meta-analysis of five trials of bupropion, the mean difference in weight loss 
was 2.77 kg (CI, 1.1 to 4.5) between bupropion and placebo groups at 6 months. White and Grilo [97] 
reported preliminary, modest support for weight loss specifically in patients with obesity and BED.
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NB Combination. The putative mechanisms of action for NB is especially relevant for reducing binge eating 
and weight per hypothesized effects on brain regions implicated in the regulation of food intake and weight 
based on research on the mechanisms of action of leptin [96]. The anorectic effects of leptin result from its 
excitatory effects on pro-opiomelanocorin (POMC) neurons in the hypothalamus melancortin system [98, 99]. 
Stimulated POMC signaling decreases food intake, increases energy expenditure, but is then inhibited by 
endogenous feedback [98]. Thus, combining these two drugs will stimulate POMC neurons (bupropion) plus 
block endogenous feedback that inhibits POMC activity (naltrexone) [47, 96]. This synergistic model received 
support both in vitro and in vivo studies [47, 100].
Obesity Outcomes. Recently, several large RCTs have reported that the combination of these two medications 
(Naltrexone/Bupropion) were effective in promoting weight loss in obese patients [47-49, 101]. These RCTs 
reported significant clinically-meaningful weight losses with sustained-release naltrexone (32 mg/day) plus 
sustained-release bupropion (360 mg/day) combined in fixed-dose tablets. Most recently, Apovian, Aronne 
[50], in a study of 1496 obese patients reported significantly greater weight losses relative to placebo (-6.5% 
vs -1.9% at week 28 and -6.4% vs -1.2% at week 56) and significantly greater likelihood of achieving 5% weight 
loss (56% vs 18% at 28 weeks and 51% vs 17% at 56 weeks). These findings supporting NB medication are 
quite consistent with earlier (large) RCTs which reported the following percentage of patients achieving at 
least 5% weight loss: 56% vs. 18% [48]; 52% vs. 15% [102]. Thus, the proposed RCT study will test the 
effectiveness of Naltrexone/Bupropion relative to placebo for reducing binge-eating and producing weight 
loss in obese patients with BED.
Risks. Several large-scale studies have found that this medication is safe and effective for the treatment of 
obesity [47-49, 101]. The NB combination approved by the FDA (Contrave) is reported to have the following 
common adverse reactions: nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), 
dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%). In addition, Contrave will have the 
FDA warnings and precautions: “Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. 
Discontinue Contrave if symptoms develop. Risk of seizure may be minimized by adhering to the 
recommended dosing schedule and avoiding coadministration with high-fat meal. Increase in Blood Pressure 
and Heart Rate: Monitor blood pressure and heart rate in all patients, especially those with cardiac or 
cerebrovascular disease. Hepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed 
with naltrexone exposure. Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with 
untreated anatomically narrow angles treated with antidepressants. Use of Antidiabetic Medications: Weight 
loss may cause hypoglycemia. Monitor blood glucose.” 
3. Source:  Identify the source of the drug or biologic to be used. 
NB will be purchased using funds awarded in this grant. 
a)
Is the drug provided free of charge to subjects? ☒YES 
☐NO 
If yes, by whom? Write here
1.
Storage, Preparation and Use: Describe the method of storage, preparation, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
 Write here
Check applicable Investigational Drug Service utilized:
    ☒  YNHH IDS                                                        ☐  CMHC Pharmacy                                           ☐ West Haven VA
    ☐  PET Center                                                      ☐    None      
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    ☐  Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation.  
2.
Use of Placebo: 
☐Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a)
Describe the safety and efficacy of other available therapies. If there are no other available therapies, state 
this. 
Expert opinion [21] and critical quantitative meta-analytic reviews [28] conclude CBT is the best-established 
treatment for BED; CBT, however, does not produce clinically meaningful weight loss and is not readily 
available given the need for specialized training. Alternative therapies include other psychological therapies 
such as interpersonal psychotherapy (which also fails to produce weight loss and is not readily available since 
it requires intensive training and few practitioners employ it) and self-help versions of CBT (which will be used 
in this study). Alternative pharmacologic therapies include antidepressant medications (SSRIs) although 
weight loss is uncertain with those agents.  
Pharmacotherapy (medications) for BED has received increased research attention albeit nearly all RCTs have 
been of short duration and without follow-up period to establish durability [20, 22]. Critical review and meta-
analysis show that several drugs – working through varied mechanisms – have short-term efficacy relative to 
placebo for reducing binge-eating and produce weight loss ranging from modest to none [20]. Placebo-
controlled trials of anticonvulsants topiramate and zonisamide [24-26] have reported effects for reducing 
both binge-eating and weight (with a mean improvement in weight loss of approximately 3-4 kg compared to 
placebo), but have also shown frequent dropout and adverse events which become nearly universal with 
longer use [27]. SSRI antidepressants, previously regarded as a potential treatment strategy [28] are 
characterized by small effect sizes relative to placebo [20] and produce no weight loss at all [38] and are 
inferior to CBT [29, 30]. 
b)
State the maximum total length of time a participant may receive placebo while on the study. 
Participants may receive placebo medication for up to 3 months if randomized to placebo. 
c)
Address the greatest potential harm that may come to a participant as a result of receiving placebo. 
Without immediate effective treatment, the greatest potential harm is that binge eating and associated 
eating disorder features may not improve. Placebo-controlled trials have rarely reported worsening and 
generally report a positive placebo response [22].
d)
Describe the procedures that are in place to safeguard participants receiving placebo. 
Possible risks include failure of binge eating and associated eating disorder features to improve. Previous 
experience suggests that the frequency of these situations is rare [22]. 
To safeguard participants, we plan to assess potential adverse events, side effects, and clinical status. All 
participants will have monthly visits with research clinicians, who can be expected to detect the clinical 
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changes that warrant concern. Participants will be removed from the study if, through the consultation of the 
PI and study physician, it is determined that participant safety is at risk, including worsening depression, 
suicidal ideation, intensification of binge eating, or failure to comply with medication. If a participant is 
removed from the study, a research clinician will provide referrals. If removal is indicated, a referral for 
appropriate care will be provided. 
3.
Continuation of Drug Therapy After Study Closure   ☐Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has ended?
☐ Yes   If yes, describe the conditions under which continued access to study drug(s) may apply as well as 
conditions for termination of such access.  Write here
☒ NO   If no, explain why this is acceptable. 
Our procedure follows existing pharmacotherapy treatment literature for BED, which has delivered 
medications in an acute, short-term manner. 
 B.  DEVICES
 ☐N/A
1.
Are there any investigational devices used or investigational procedures performed at Yale-New Haven 
Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and Vascular Center)?  ☐Yes   ☒No   
 If Yes, please be aware of the following requirements:
A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the Tools tab in the EPIC Banner, 
Click on Lawson, Click on “Add new” under the New Technology Request Summary and fill out the forms 
requested including the “Initial Request Form,” “Clinical Evidence Summary”, and attach any other pertinent 
documents. Then select “save and submit” to submit your request;   AND
Your request must be reviewed and approved in writing by the appropriate YNHH committee before 
patients/subjects may be scheduled to receive the investigational device or investigational procedure.
2.
Background Information: Provide a description of previous human use, known risks, and any other factors 
that might influence risks. If this is the first time this device is being used in humans, include relevant data on 
animal models. 
We are developing the Biosensor program that facilitates continuous passive monitoring of eating behavior 
and stress using wristband mounted sensors. 
To monitor ambulatory stress levels, we will use Garmin bands. These bands provide a ‘stress score’ (range 1-
100) with a 3-minute granularity. The algorithm is proprietary, but Garmin acknowledges that one of the 
primary factors in the algorithm is heart rate variability (HRV). HRV is the beat-to-beat variation in heart rate, 
which has been shown to be associated with emotion regulation and likely contribute to binge eating101.  The 
Garmin band also provides daily metrics on steps, distance, heart rate, sleep duration, and sleep level 
classification. Access to this data is through a Garmin service to academic researchers 
https://developer.garmin.com/health-api/overview/. Data obtained from bands will be continuously 
transmitted to the mHealth Core Facility at UMass. The mHealth Core Facility at the University of 
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Massachusetts will assist with the collection of electronic data, transmitting and storage of the data, and 
providing collected and processed data to Yale. This data collection system (which integrates the Garmin 
Band data collection and the smartphone data collection) is being developed for the Yale-SCORE 
(HIC#2000023970; PI, McKee). All data collected will be de-identified. 
Physical discomfort from wristband. Participants will be outfitted with wrist worn bracelets with integrated 
sensors. While there is potential physical discomfort associated with regular wearing of a wristband, our 
experience in the pilot study suggests that this has been minimal and subjects have been comfortable 
wearing the device for extended periods.  
3.
Source: 
a) Identify the source of the device to be used. 
The Garmin bands are available to the public for purchase and will be purchased by the Research 
Team.  A compatible Android phone will be provided by the Research Team for participant use throughout 
the 6-weeks.
b) Is the device provided free of charge to subjects? ☒Yes   ☐No    
4.
Investigational device accountability:  State how the PI, or named designee, ensures that an investigational 
device is used only in accordance with the research protocol approved by the HIC, and maintains control of 
the investigational device as follows:
a)
Maintains appropriate records, including receipt of shipment, inventory at the site, dispensation or use 
by each participant, and final disposition and/or the return of the investigational device (or other 
disposal if applicable): All packages shipped to Yale containing equipment will be tracked using the 
shipper’s tracking numbers. A log of materials received will be kept and a corresponding de-identified log 
will be kept to track items given to each participant. Participants will receive payment for completing the 
Biosensor portion of the study once the Biosensor has been returned to the Research Team.   
b)
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch or 
serial number, expiration date if applicable, and unique code number): A log of materials received will be 
kept and will include any pertinent information needed to identify each device.
c)
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations: The Biosensor will be stored in 
a locked cabinet in a locked office.
d)
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements: The locked cabinet where the Biosensors will be stored is located in a locked 
office within our locked suite. Only members of the Research Team have access to this area.
e)
Distributes the investigational device to subjects enrolled in the IRB-approved protocol: Subjects will not 
receive the Biosensor until they have reviewed/agreed/signed a Consent Form, completed the intake 
process to determine eligibility, and completed the first lab session. Only a subset (n=60) will participate.
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 
a.
Targeted for enrollment at Yale for this protocol: N=200
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b.
If this is a multi-site study, give the total number of subjects targeted across all sites: n/a
2.
Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
☒Flyers
☒ Internet/web postings
☐ Radio
☒ Posters
☐ Mass email solicitation
☒ Telephone
☐ Letter
☒ Departmental/Center website
☒ Television
☐ Medical record review* 
☐ Departmental/Center research boards
☒ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☒ Clinicaltrails.gov 
☒ YCCI Recruitment database
☐ Social Media (Twitter/Facebook): 
☐ Other: EPIC direct to patient
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified. 
Participants will be recruited using ads and flyers placed in local media (newspapers and television), and 
internet and printed materials throughout the community. We will also work with YCCI using their 
recruitment strategies, including distribution of materials throughout the community, email and internet 
solicitation, working with community contacts, and receiving information about potential participants YCCI 
identified as interested in research related to our topics (obesity, binge eating disorder, mental and physical 
health). 
Biosensor Arm: Participants who are interested in or currently enrolled in any study with the research team 
can be contacted to see if they are interested in participating in this Biosensor Study alone or in conjunction 
with the study they are currently enrolled in. Participants will follow the same screening, recruiting and 
consenting procedures as described below in person or remotely (i.e., Zoom). Participants enrolled in the 
study will be contacted and offered the biosensor arm. Participants not enrolled in the RCT will only be 
contacted if we have permission to contact them about future studies.   
b. Describe how potential subjects are contacted. 
Advertisements will ask participants to contact our research team if they are interested in the study. When 
potential participants call (or, if preferred by the participant, through the Yale Qualtrics system), they will be 
screened to determine whether they are likely to be eligible. If they seem potentially eligible and interested, 
they will be scheduled for an initial assessment. 
c. Who is recruiting potential subjects? 
After initial contact, research clinicians (who have completed IRB training) will meet with potential 
participants to discuss the study, the treatments, the assessments, the follow-up period, and the informed 
consent procedures and forms. Clinicians will answer any questions and obtain written informed consent. A 
copy of the signed informed consent form will be given to the participants and the original will be kept in the 
participant's file. All potential subjects and/or participating participants are free to decide whether or not to 
participate and are free to withdraw from the study at any time. Alternative treatments would be discussed 
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and/or referrals provided. A decision not to participate or to discontinue participation would not adversely 
affect future interactions with Yale or the Yale School of Medicine.
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship with any 
potential subject? 
☐Yes, all subjects
☐Yes, some of the subjects
☒No
If yes, describe the nature of this relationship. Write here
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of this 
data:  
Participants will initially call us and/or contact us through an online form in response to 
advertisements, at which time, if they seem eligible, we will schedule them for an initial assessment 
and collect contact information. We will also request that patients complete online surveys. If 
potential participants elect to participate, they would then provide informed consent including HIPAA 
authorization as described at their initial in-person visit. Names will be removed from surveys if an 
individual does not provide informed consent.
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: Write here
The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, except 
as required by law, for authorized oversight of this research study, or as specifically approved for use in another 
study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6.
Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making. 
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At the start of the initial intake evaluation, participants will provide written consent to participate in a 
research project and treatment. Informed consent will be collected at 301 Cedar Street, 2 Church St South or 
remotely (via Zoom). Participants will sign the electronic consent via RedCap (Yale’s aproved platform). 
Clinicians will answer any questions that participants may have. Alternative treatments would be discussed 
and/or referrals provided. Participants will be informed that a decision to not participate or to discontinue 
participation would not adversely affect future interactions with Yale or the Yale School of Medicine. 
Participants also will be informed that their participation is strictly voluntary, and that they may withdraw at 
any time with no penalty.
Participants interested in the Biosensor Arm will complete a separate consent.
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel obtaining 
consent will assess the potential subject’s ability and capacity to consent to the research being proposed. 
With all participants, we will describe the study verbally during the consent process, and allow participants to 
ask any questions they might have. To ensure understanding, we will use open-ended questions with all 
participants to ask that they paraphrase the nature of the research and what they are being asked to do as 
part of the study, and also summarize the potential risks and benefits of the study. 
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent 
materials must be submitted for approval prior to use. 
n/a
As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation of 
the long form is not possible prior to intended enrollment?  YES ☐  NO ☐
Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject.   Please review the guidance and presentation on use of 
the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA waiver in 
the section above. 
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver 
of consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed consent 
for this study, complete the appropriate section below.  
☐Not Requesting any consent waivers 
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☐Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study (Note that an information sheet may be required.)
 For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research?  YES ☐  NO ☒ 
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒  NO ☐
 
OR
Does the research pose greater than minimal risk? YES ☐    NO☒ 
Does the research include any activities that would require signed consent in a non-research context? YES ☐   
NO ☒
 ☐ Requesting a waiver of consent:
☐ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study 
 
For a full waiver of consent, please address all of the following:

Does the research pose greater than minimal risk to subjects?  
☐ Yes If you answered yes, stop. A waiver cannot be granted.  
☐ No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐    NO☐

Why would the research be impracticable to conduct without the waiver? Write here

Where appropriate, how will pertinent information be returned to, or shared with subjects at a later date? 
Write here
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research?   
Height, weight, medical and psychosocial history will be collected and used for research.
2.
How will the research data be collected, recorded and stored? 
All participants will be assigned a study number. Subsequently, participants will be identified only by that 
number. A list of numbers and the corresponding names will be maintained by investigators on a protected 
research server. Any identifying information that is collected on paper will be kept in locked research cabinets 
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within a locked suite. Interviews will be recorded using a digital recorder and recordings will be securely and 
separately stored and be identified only by a study number and date. 
Any information published as a result of the study will be such that it will not permit identification of any 
participant. All information collected will remain confidential except when we are legally required to disclose 
such information by law. These circumstances include knowledge of abuse of a child or elderly person, threats 
of harm to self or others, and plans to harm to property. 
3.
How will the digital data be stored? ☐CD  ☐DVD  ☐Flash Drive  ☐Portable Hard Drive   ☒Secured Server  
☐Laptop Computer  ☐Desktop Computer  ☐Other
4.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study? 
See above, the patients will only be identified by a number on any digital data files. Individually identifiable 
health information will be protected in accordance with the Health Insurance Portability and Accountability 
Act of 1996.
All portable devices must contain encryption software, per University Policy 5100.  If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and Compliance 
Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
5.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data and/or 
identifiers will be secured. 
Data will continue to be stored in locked cabinets in limited access areas until the legal requirement for 
storage has been met. Electronic data files will be password protected. Electronic data files will include code 
numbers only – i.e., will not contain patient identifying information. 
6.
If appropriate, has a Certificate of Confidentiality been obtained? Yes
SECTION V: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.) 
Participation in the study has the potential to result in decreased frequency of binge eating and weight loss 
for at least some patients through free assessments and treatment. More generally, the low risk is offset by 
the potential of identifying effective behavioral and pharmacological treatments for reducing binge eating 
and weight in obese persons with binge eating disorder, which would be beneficial to many persons who 
experience these conditions.
Participation in the Biosensor Arm carries low risk, which is offset by the potential knowledge to be gained 
about identifying triggers of binge eating episodes and connections between stress and eating behavior, 
which would be beneficial to many people who experience binge eating.
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         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
Alternatives include community referrals for cognitive behavioral therapy, behavioral weight loss, or 
medications. 
2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation.
Clinical trial assessments. Participants will be paid when they complete the assessments at the end of the 
treatment ($100), 6-Month Follow-up ($100), and 12-Month Follow-up ($100). Participants who drop out of 
the trial will be invited to return for the follow-up evaluations. At each assessment, conditions for receiving 
compensation include completion of surveys, bloodwork, and interview. 
Lab sessions. Participants will receive additional payment when they complete human laboratory sessions 
pre-treatment ($200) and at the end of treatment ($200). Participants can also earn up to $31.50 during each 
lab session if they chose to delay the full 180 minutes. 
Month 1 Blood Draw. Participants will receive additional payment when they complete their blood draw one 
month into treatment ($10). 
Biosensor. Participants who are part of the 6-week assessment with biosensor equipment can earn up to 
$300 if they complete all assessments and return the equipment. Participants can earn up to $300 for 
wearing the Garmin band and responding to the prompts daily for the 6 weeks (42 days). Participants can 
earn $6 per day if they respond to all prompts. If they do not respond to 90% of the prompts each day, they 
will earn $0.50 for each prompt they did respond to that day. The Garmin bands and Android phones must be 
returned to the Research Team at the end of the 6-weeks. Once the participant has completed the 6-weeks 
and returned the equipment, they will earn a $48 Completion/Return Bonus. If the Garmin band and/or 
phone are not returned, the participant will keep the items in lieu of payment and will not receive any 
additional compensation.   
Therefore, the total payment participants may receive is up to $1073. Our experience with numerous 
treatment and human laboratory studies has indicated that this incentive results in a high retention rate for 
follow-ups which is essential for the study. 
Subjects will be compensated for parking for research study appointments at the HRU/CSRU. They must show 
their parking ticket to the Research Staff for verification. Parking tickets will be returned to the subject so they 
are able to exit the parking lots and they will sign a Parking Voucher for the money received.  
Biosensor Arm: Participants that complete the 6-week assessment with the biosensor equipment can earn up 
to $402 if they complete all assessments and return the equipment. Participants will receive $25 for 
completing the baseline set of questionnaires and $25 for completing the final set of questionnaires. They can 
earn up to $252 for wearing the Garmin band and responding to the prompts daily for the 6 weeks (42 days). 
Participants can earn $6 per day if they respond to all prompts. If they do not respond to 80% of the prompts 
each day, they will earn $0.50 for each prompt they did respond to that day. The Garmin bands and Android 
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phones must be returned to the Research Team at the end of the 6-weeks. Once the participant has 
completed the 6-weeks and returned the equipment, they will earn a $100 Completion/Return Bonus. If the 
Garmin band and/or phone are not returned, the participant will keep the items in lieu of payment and will 
not receive any additional compensation.   
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs associated with 
participation in the research, and the interventions or procedures of the study that will be provided at no cost 
to subjects. 
Psychological assessment, labwork, and treatment will be provided at no cost to participants, their insurance, 
health plan benefits nor other third party payer. Participants will be asked to provide information from a 
recent (within one year) physical with their primary healthcare provider. If they have not had a physical within 
the past year, we will ask them to obtain a physical prior to participating in the study. A physical exam with 
their own primary healthcare provider would be at the participant’s (or the participant’s insurance) cost. 
(Note: In research we have conducted in the past with patients diagnosed with binge eating disorder, the 
majority of patients had a physical within the past year.) 
Biosensor Arm: Participants will be provided with the Garmin band and the Android smartphone to use for 
the 6-week monitoring period at no cost. 
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? 
Yes. Referrals for treatment will be made.
b.
Where and from whom may treatment be obtained? 
If the participant is injured as a direct result of participation in this research study, the medical 
staff at the Yale-New Haven Hospital would be available to provide immediate emergency care, 
short-term hospitalization and/or short-term outpatient care. 
c.
Are there any limits to the treatment being provided? 
If the participant is injured as a direct result of participation in this research study, the treatment 
will be determined by the medical provider(s). 
d.
Who will pay for this treatment? 
The participant or participant’s insurance carrier will be billed for the cost of this treatment. 
There are no plans to compensate the participant for physical or mental disability, lost wages, or 
any other losses or damages occurring over the long term or if an injury becomes apparent after 
participation in the study has ended. However, by agreeing to participate in this research study, 
the participant is not waiving or giving up any legal rights to seek compensation. Participants who 
believe they have been injured should contact the Principal Investigator, Dr. Carlos Grilo at 203-
785-2792 immediately. 
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e.
How will the medical treatment be accessed by subjects? 
Referrals will be provided.
IMPORTANT REMINDERS
Will this study have a billable service?  Yes ☒ 
 No☐
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, would 
normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s 
insurer. The service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no distinction made 
whether the service is paid for by the subject or their insurance (Standard of Care) or by the study’s funding 
mechanism (Research Sponsored). 2. This generally includes new services or orders placed in EPIC for research 
subjects. 
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research management system, for 
Epic to appropriately route research related charges. Please contact oncore.support@yale.edu
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities?  
Yes ☒  No ☐ 
If Yes, please answer questions a through c and note instructions below.  
a. Does your YNHH privilege delineation currently include the specific procedure that you will perform? Yes ☒  No 
☐
b. Will you be using any new equipment or equipment that you have not used in the past for this procedure? Yes 
☐  No ☒
c. Will a novel approach using existing equipment be applied? Yes ☐  No ☒
 
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department of 
Physician Services (688-2615) for prior approval before commencing with your research protocol.
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the HRU, the 
Principal Investigator and any co-investigators who are physicians or mid-level practitioners (includes PAs, APRNs, 
psychologists and speech pathologists) who may have direct patient contact with patients on YNHH premises 
must have medical staff appointment and appropriate clinical privileges at YNHH. If you are uncertain whether 
the study personnel meet the criteria, please telephone the Physician Services Department at 203-688-2615. By 
submitting this protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
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