Clinical trial NCT03063606
Conditions: Binge-Eating Disorder Obesity
Sponsor: Yale University
Start date: 2017-09-05; Completion date: 2022-12-16
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test the effectiveness of cognitive-behavioral therapy as a specialist treatment for binge eating disorder (BED) in patients with obesity. This is a controlled test of whether, amongst non-responders to acute treatments, cognitive-behavioral therapy augments on-going blinded pharmacotherapy (either naltrexone/bupropion or placebo), compared with no additional behavioral treatment .

Detailed description:
Binge eating disorder (BED), the most prevalent formal eating disorder, is associated strongly with obesity and bio-psychosocial impairment. Improved treatments for patients with obesity and BED are needed that can produce sustained clinical outcomes and promote weight loss. This study (specialist treatment) RCT will provide new and novel findings from a controlled test, amongst non-responders to acute treatments, whether cognitive-behavioral therapy augments on-going blinded pharmacotherapy (naltrexone/bupropion or placebo) compared with on-going pharmacotherapy alone (without added cognitive-behavioral therapy).

Arms: arm 1: CBT is a "specialist" focal treatment with three overlapping phases. (1) Establishing a collaborative therapeutic relationship while focusing on educating patients about the nature of binge eating and factors thought to maintain the problem. Specific behavioral strategies (e.g., self-monitoring) are used to help patients identify problematic eating behaviors while establishing a normal structured eating pattern. (2) Integrating cognitive restructuring procedures, focusing on helping patients learn to identify and challenge maladaptive cognitions regarding eating and weight/shape and thoughts that trigger binge eating. (3) Maintaining change and preventing relapse. arm 2: Participants will continue acute blinded pharmacotherapy (consisting of either naltrexone/bupropion combination or placebo), but without added cognitive-behavioral therapy.
Interventions: intervention 1: Cognitive-Behavioral Therapy (CBT) intervention 2: NB Medication (on-going from acute treatment)
Intervention descriptions: intervention 1: CBT specialist treatment intervention 2: Naltrexone/bupropion combination (on-going blinded pharmacotherapy from acute treatment consisting of either naltrexone/bupropion or placebo)

Protocol documents:
Prot_SAP_000.pdf: 
NCT03063606 
Behavioral and Pharmacologic Treatment of Binge Eating and Obesity 
Document date: 10/28/2020 


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YALE UNIVERSITY
                 HUMAN INVESTIGATION COMMITTEE
                   Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: 
1506016065 - Behavioral and Pharmacologic Treatment of Binge Eating and Obesity 
Principal Investigator:
Carlos M. Grilo, Ph.D.
Yale Academic Appointment:
Professor of Psychiatry and Psychology
Director of Yale Program for Obesity, Weight, and 
Eating Research
Department: Psychiatry and Psychology
Campus Address: 
301 Cedar St., 2nd Floor. New Haven, CT 06520
Campus Phone: 5-2792
Fax: 5-7855
Pager: 
E-mail: carlos.grilo@yale.edu
Protocol Correspondent Name & Address (if different than PI):
 Janet Lydecker, Ph.D.
Campus Phone: 7-4299
Fax: 5-7855
E-mail: janet.lydecker@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): 
 N/A
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Date: 10/7/2020, Version 11
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)      
 N/A
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
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degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
 Yes
 No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
 Yes
 No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form: http://www.yale.edu/coi/ 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel. Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations: Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research. Choose all that apply:
 
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center 
(MR-TAC)
Yale Cancer Center/Clinical Trials 
Office (CTO)
Yale Cancer Center/Smilow
Yale-New Haven Hospital
Cancer Data Repository/Tumor Registry
Yale University PET Center
YCCI/Church Street Research Unit 
(CSRU)
YCCI/Hospital Research Unit (HRU)
YCCI/Keck Laboratories
Yale-New Haven Hospital—Saint 
Raphael Campus
Other Yale Location: Yale Program for Obesity, Weight, and Eating Research, 301 
Cedar St, 2nd Floor; Yale Department of Psychiatry
b. External Location[s]:
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APT Foundation, Inc.
Connecticut Mental Health Center
Clinical Neuroscience Research Unit 
(CNRU)
Haskins Laboratories
John B. Pierce Laboratory, Inc.
Veterans Affairs Hospital, West 
Haven 
 Other Location: Quest Diagnostics
International Research Site 
Lawrence-Memorial Hospital
(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Yale University RSC (YU-RSC)
Approval Date:
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date:
 *Nursing Research Committee
Approval Date:
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) 
found at  http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See 
instructions for documents required for initial submission and approval of the protocol. 
Allow sufficient time for these requests. Check with the oversight body for their time 
requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 
September 2016 – September 2023
3. Research Type/Phase: (Check all that apply)
a. Study Type
  
 Single Center Study
  
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
 
 Coordinating Center/Data Management
 
 Other: 
b. Study Phase
 N/A
  
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
  
 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c:
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 Clinical Research: Patient-
Oriented
 
 
 Clinical Research: Epidemiologic 
and Behavioral 
     
   
 Translational Research #1 
(“Bench-to-Bedside”)   
 Translational Research #2 
(“Bedside-to-Community”) 
 Clinical Research: Outcomes and 
Health Services
 Interdisciplinary Research
 Community-Based Research
5.  Is this study a clinical trial? 
Yes 
 No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of 
a clinical trial: “any research study that prospectively assigns human participants or groups 
of humans to one or more health-related interventions to evaluate the effects on health 
outcomes.” Health-related interventions include any intervention used to modify a 
biomedical or health-related outcome (for example, drugs, surgical procedures, devices, 
behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes 
include any biomedical or health-related measures obtained in patients or participants, 
including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the 
ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and 
compound authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? 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 
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mechanism (Research Sponsored). 2. This generally includes new services or orders placed 
in EPIC for research subjects. 
Yes 
 No
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
8. 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. If No, proceed to 
Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you 
will perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
c. Will a novel approach using existing equipment be applied?
 
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with 
your research protocol.
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 signing 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.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that 
apply. Provide information regarding the external funding source. This information should 
include identification of the agency/sponsor, the funding mechanism (grant or contract), and 
whether the award is pending or has been awarded. Provide the M/C# and Agency name (if 
grant-funded). If the funding source associated with a protocol is “pending” at the time of 
the protocol submission to the HIC (as is the case for most NIH submissions), the PI should 
note “Pending” in the appropriate section of the protocol application, provide the M/C# and 
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Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made). 
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Carlos M. 
Grilo
Behavioral and 
Pharmacologic 
Treatment of Binge 
Eating and Obesity
NIH/ NIDDK
 Federal
 State
 Non Profit
 Industry
 Other For 
Profit 
 Other
Grant-M# 
2 R01 DK49587-16     
Contract# 
Contract Pending
 Investigator/Department 
Initiated
 Sponsor Initiated
 Other, Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors. 
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent. Note: the PI’s home department will be billed if this information is not provided. 
 N/A
Send IRB Review Fee Invoice To: 
Name:
Company:
Address:
Research Team: Please see IRES. 
SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the 
research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating 
the study or any change and I will obtain continuing approval of this study prior to the expiration 
date of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants.

I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the Dean’s 
Office or Office of the Provost, or the Human Subject Protection Administrator at Yale-New 
Haven Hospital, or have a faculty advisor.
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
I will identify a qualified successor should I cease my role as principal investigator and facilitate 
a smooth transfer of investigator responsibilities.
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of 
human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions 
prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated    
problems involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as    the 
faculty advisor of this project. 

I assume all of the roles and responsibilities of a Principal Investigator even though the student 
may be called a PI.
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SECTION V: RESEARCH PLAN
A. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
This study aims to perform a two-stage randomized controlled trial to test the effectiveness of 
behavioral weight loss (BWL) and pharmacotherapy (Naltrexone/Bupropion; NB), alone and in 
combination, for the treatment of binge eating disorder (BED) in patients with obesity. 
Figure 1. Research design of two-stage trial of BWL and NB for BED in patients with obesity
The first stage will examine the effectiveness of NB medication with and without BWL in 
reducing both binge eating and weight (See Figure 1). 
(1) Stage 1 RCT – Primary Aim - Test effectiveness of BWL and NB medication, alone and 
combined, for BED. Primary aims are to evaluate the effectiveness for (a) reducing binge 
eating and (b) reducing weight.
(2) Stage 1 RCT – Secondary Aims: (a) Examine effectiveness of BWL and NB medication, 
alone and combined, on secondary outcomes: remission (zero binges/ 28 days), eating-
disorder pathology, depression; and (b) Explore predictors, moderators, and mediators of 
primary outcomes.
The second stage will examine whether continued NB medication results in superior 
maintenance and longer-term outcomes than placebo amongst responders to Stage 1 
treatments. The second stage will also explore whether adding cognitive-behavioral therapy 
(CBT) enhances on-going pharmacotherapy (NB/placebo), amongst non-responders to Stage 1 
treatments (See Figure 1). 
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(3) Stage 2 RCT – Secondary Aims: Examine the effectiveness of NB medication amongst 
responders to Stage 1 treatments for enhancing maintenance and longer-term (a) change in 
binge eating frequency and (b) weight change.
(4) Stage 2 RCT – Exploratory Aims: (a) Explore the effectiveness of NB medication on 
secondary outcomes: relapse to BED threshold, eating pathology, depression, psychosocial 
and metabolic functioning; and (b) Explore whether Stage 1 treatment moderates 
medication effects during Stage 2.
(5) Stage 2 RCT – Exploratory Aim: CBT for Non-Responders: Explore, amongst Non-
responders to Stage 1 treatments, whether adding CBT enhances on-going NB 
pharmacotherapy.
B. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
Obesity (OB) is a refractory, serious public health problem, and an estimated 34% of 
U.S. adults have obesity (Flegal, Carroll, Ogden, & Curtin, 2010). This study proposes 
to test treatments for a high-risk subgroup of adults with OB, adults with binge-eating 
disorder (BED) and OB (Hudson, Hiripi, Pope, & Kessler, 2007). 
Binge-Eating Disorder (BED) – A Clinical Subgroup of People with Obesity
BED is a formal diagnosis in the DSM-5 (American Psychiatric Association, 2013). BED 
is defined by recurrent episodes of binge eating (eating an unusually large amount of 
while experiencing a subjective sense of loss of control) without compensatory weight 
control methods (e.g., self-induced vomiting) that characterize bulimia nervosa. The 
BED diagnosis requires binge eating to be associated with marked distress. 
Epidemiologic studies have found that BED is more prevalent than anorexia and bulimia 
nervosa (Hudson et al., 2007; Kessler et al., 2013). The prevalence of BED in the 
National Co-morbidity Survey Replication (Hudson et al., 2007) was 3.5% among 
women and 2.0% among men. Estimates of BED are higher in adults with obesity (8%) 
and much higher in most clinical settings (Johnson, Spitzer, & Williams, 2001; Wilfley, 
Wilson, & Agras, 2003). Compared to other eating disorders, BED is prevalent across 
gender and ethnic/racial groups (Marques et al., 2011). BED has diagnostic validity 
(Striegel-Moore & Franko, 2008), is a stable construct (Pope et al., 2006), differs from 
other eating disorders and obesity (Allison, Grilo, Masheb, & Stunkard, 2005; Grilo et 
al., 2009; Grilo, Masheb, & White, 2010) and is strongly associated with obesity 
(Kessler et al., 2013) and elevated risk for medical, psychiatric, and psychosocial 
problems (Grilo et al., 2009; Grilo et al., 2010; Hudson et al., 2007; Hudson et al., 
2010). 
Treatment for BED: Current Status and Future Needs 
Overall, several medications have short-term efficacy relative to placebo (Reas & Grilo, 
2008) and certain psychological treatments have efficacy (Wilson, Grilo, & Vitousek, 
2007) with important advantages over medication (alone or in combination) (Reas & 
Grilo, 2008). 
Cognitive Behavioral Therapy (CBT) is the best-established treatment for BED 
(National Institutes of Clinical Excellence, 2004; Wilson et al., 2007). RCTs testing CBT 
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report roughly 50% remission rates from binge eating (Grilo, Masheb, & Wilson, 2005; 
Grilo, Masheb, Wilson, Gueorguieva, & White, 2011). Improvements in binge eating are 
significantly superior to fluoxetine (Grilo, Masheb, & Wilson, 2005) and fluvoxamine 
(Ricca et al., 2001) and are durable for 12-months after CBT (Grilo, Crosby, Wilson, & 
Masheb, 2012). RCTs have provided further support for “specific” efficacy of CBT for 
BED, although CBT fails to produce weight loss (Grilo et al., 2011). The association 
between BED and obesity (Hudson et al., 2007) and possible heightened risk for 
developing future metabolic problems (Hudson et al., 2010) highlight the need to find 
methods to reduce weight–and binge eating–in this subgroup of people with obesity. 
Behavioral Weight Loss (BWL) for BED may be more effective than CBT for 
producing weight loss while achieving comparable reductions in binge eating that are 
maintained through 12-month follow-ups (Grilo et al., 2011). Although longer-term 
follow-up suggests that improvements in binge eating and weight losses are less 
durable in BWL (Wilson, Wilfley, Agras, & Bryson, 2010), BWL is more widely available 
and has greater dissemination than “specialist” CBT methods, which are very limited in 
availability (Hart, Granillo, Jorm, & Paxton, 2011; Kazdin & Blase, 2011; Shafran et al., 
2009; Wilson & Zandberg, 2012). BWL has the advantage of being available in many 
health service settings and delivered by diverse allied health-care workers (i.e., not just 
“specialists” and doctoral-level clinicians with CBT training). This is especially relevant 
for BED because few individuals with BED receive mental health services (Marques et 
al., 2011) and especially fewer receive specialist treatment (Wilson & Zandberg, 2012). 
Pharmacotherapy for BED has received research attention, albeit nearly all RCTs 
have been of short duration and without follow-up period to establish durability (Reas & 
Grilo, 2008, 2014, 2015). 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 (Reas & 
Grilo, 2008). Placebo-controlled trials of anticonvulsants topiramate and zonisamide 
(Claudino et al., 2007; McElroy et al., 2003; McElroy et al., 2006) 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 (McElroy, Kotwal, Hudson, 
Nelson, & Keck, 2004). SSRI antidepressants, initially regarded as a potential treatment 
strategy (e.g., National Institutes of Clinical Excellence, 2004) are characterized by 
small effect sizes relative to placebo (Reas & Grilo, 2008), produce no weight loss at all 
(Grilo, Masheb, & Wilson, 2005) and are inferior to CBT (Grilo, Masheb, & Wilson, 2005; 
Ricca et al., 2001). 
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 (McElroy et al., 2016; McElroy et al., 2015) 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 (McElroy et al., 2016) are less robust than those reliably produced by BWL 
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for BED, and BWL outcomes are durable through 12-months post-treatment (Grilo, 
Masheb, & Crosby, 2012). Most importantly, although LDX was associated with weight 
loss (mean 4.9 kg) (McElroy et al., 2015), 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 (Appolinario et al., 2003; Wilfley et al., 2008), 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 (Vetter, 
Faulconbridge, Webb, & Wadden, 2010), until 2012. Placebo-controlled trials of orlistat 
for BED (Golay et al., 2005; Grilo, Masheb, & Salant, 2005) 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 (Grilo & White, 2013). 
The 2012 FDA approval of two new anti-obesity medications (phentermine/ 
topiramate and lorcaserin) (Colman et al., 2012; Miller, 2013) came after heated debate 
given significant concerns about limited efficacy and safety profiles, and questions 
about serious medical complications with longer use (Colman et al., 2012; Miller, 2013). 
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) (Smith et al., 2010). 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.
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 (page 30).
Obesity Outcomes. Several large RCTs have reported that NB was effective in 
promoting significant, clinically-meaningful weight loss in patients with obesity 
(Greenway et al., 2010; Greenway, Whitehouse, et al., 2009; Smith et al., 2013). NB 
showed greater weight loss than placebo, -6.5 vs -1.2% (Greenway et al., 2010); -8.2% 
vs -2.1% (Smith et al., 2013), and the following percentages achieving 5% weight loss: 
56% vs. 18% (Smith et al., 2013), 52% vs. 15% (Greenway et al., 2010). Apovian et al. 
(2013), 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).
C. 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 
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include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
Figure 2. Participant Assessment and Classification Time Course.
Response to 
Recruitment
Pre-Screening
Baseline 
Assessment
Initial 
Randomization
Participation in 
Stage 1
Stage 1 Post 
Assessment
Classification 
as Responder 
or Non-
Responder
Response-
based 
Randomization
Participation in 
Stage 2
Stage 2 Post 
Assessment
6-Month 
Follow-up 
Assessment
12-Month 
Follow-Up 
Assessment
Pre-Screening: Participants responding to recruitment efforts (see page 36) will be 
screened by telephone. If participants prefer to answer some of the screening questions 
through the Yale Qualtrics system, participants will indicate their consent to the 
recruitment/screening process in the online system. Potentially eligible participants will 
be consented and evaluated in-person by trained doctoral clinicians. Participants will 
complete survey measures of eating behaviors and psychopathology and psychosocial 
functioning around the time of the in-person appointment.
Participants who provide informed consent and are determined to be eligible (see page 
21) will then participate in the study as depicted and described in the following 
paragraphs. See also Figure 1 (page 8).
Baseline Assessment: As part of the determination of eligibility (for full criteria, see 
page 21), participants will complete two interviews, the MINI International 
Neuropsychiatric Interview-Version 7.0 (MINI) and Eating Disorder Examination (EDE) 
to generate psychiatric diagnoses and detailed current eating disorder features and 
diagnoses. Other measures, for safety and establishment of baseline values, will also 
be obtained: BMI, blood pressure, heart rate, eating behaviors and psychopathology, 
psychosocial functioning, metabolic measures, and perception of treatment measures. 
For a full description of instruments, see “Measures,” which includes a grid depicting 
when each measure is administered (page 15). The baseline assessment will occur 
over two in-person meetings and is estimated to be take a total of 2-3 hours in-person. 
Study Intervention: This study will be a two-stage randomized placebo-controlled trial 
with patients who have both BED and obesity. Throughout the study, participants and all 
study staff, including investigators and outcome assessors, will be blind to the 
pharmacotherapy treatment condition, and outcome assessors will also be blind to the 
behavioral treatment condition. Stage 1 will test the effectiveness of BWL and NB 
medication, alone and in combination. Stage 2 will test the effectiveness of NB 
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medication for enhancing maintenance and longer-term outcomes (amongst 
responders). Stage 2 will also explore whether adding CBT enhances on-going NB 
pharmacotherapy (amongst non-responders). See Figure 1 on page 8.
Randomization to Stage 1 Treatment: Eligible participants (determined at the end of 
the baseline assessment according to inclusion/exclusion criteria as described on page 
21) who agree to participate and provide written informed consent will be randomized to 
one of the four treatments. N=160 patients with obesity and BED will be randomly 
assigned in balanced factorial (2 X 2) design, to one of four 16-week methods: 
BWL+NB, BWL+Placebo, NB, or Placebo. 
We will use blocked randomization with random block sizes of 4 and 8 for Stage 1 to 
obviate any secular trends. We will monitor the randomization procedure and determine 
whether systematic differences in demographic characteristics (age, gender, race/ 
ethnicity) or clinical characteristics (BMI, binge-eating frequency, psychiatric co-
morbidity) become evident. We will consider adjustment to randomization if indicated 
(Kraemer & Fendt, 1990; Kraemer & Pruyn, 1990). 
Stage 1 Treatment Protocols:
Treatment Protocol for Naltrexone/Bupropion (NB) Pharmacotherapy: Medication 
will be prescribed per FDA-approved guidelines for obesity and as used in previous 
RCTs demonstrating effectiveness of NB medication for weight loss in patients with 
obesity (Greenway et al., 2010; Greenway, Whitehouse, et al., 2009; Smith et al., 2013; 
Wadden et al., 2011). 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). 
Following regimens in previous RCTs, a dose escalation approach will be used, 
beginning with a quarter of the full dose and increasing weekly until the full dose is 
achieved at week 4 (Greenway et al., 2010; Wadden et al., 2011). This dose will 
continue for the remainder of the trial. If a patient develops intolerable side effects, the 
study physician may reduce the dose 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. 
Participants will meet with the study physician at the start of treatment. The brief 
visit (10 minutes) will focus on compliance and evaluating side effects. Participants will 
meet monthly with study staff throughout Stage 1 treatment.
Treatment Protocol for Behavioral Weight Loss (BWL): The BWL treatment is a 
mixture of the published LEARN behavioral lifestyle weight control treatment developed 
by Brownell (2000) and the Diabetes Prevention Program (Knowler et al., 2002); the PI 
and research team has extensive experience administering BWL with patients with BED 
and obesity. BWL will be delivered weekly by research-clinicians according to treatment 
manuals that detail session-by-session procedures. These manuals closely parallel 
patient-version BWL self-care materials for the entire course of treatment and follow 
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closely that used by Wadden et al. (2011) in the COR-BMOD Trial testing BWL and 
NB/placebo medication for obesity. BWL will instruct patients in developing and 
maintaining a balanced deficit diet comprised of roughly 20% protein, 30% max of fat, 
and 50% carbohydrate, with general goals of 1500kcal/day. Behavioral strategies (goal-
setting, self-monitoring, stimulus control problem-solving) will be taught within a lifestyle 
approach for achieving dietary goals (augmented by portion size and caloric goals) and 
physical activity goals (to achieve 180 min/week of moderate physical activity). 
Research-clinicians will be trained in BWL by the research team and will be supervised 
and monitored over the course of treatment delivery to ensure quality adherence.
Stage 1 Post Assessment: After completing Stage 1 treatment (BWL+NB, 
BWL+Placebo, NB, or Placebo), participants will complete an assessment, the EDE, to 
assess for binge-eating episode frequency. Based on this interview, participants will be 
classified as “responders” (65% or greater reduction in binge-eating episodes, per 
findings suggesting prognostic significance of such responses) (Grilo, Masheb, & 
Wilson, 2006; Grilo, White, Wilson, Gueorguieva, & Masheb, 2012) or “non-responders.” 
Other measures are described in the “Measures” grid that depicts when each measure 
is administered (page 15). 
Randomization to Stage 2 Treatments:
“Responders” to acute treatments (65% or greater reduction in binge eating) 
will be randomized to NB or placebo for 16 weeks of maintenance pharmacotherapy. 
Participants and investigators will remain blind to pharmacotherapy condition. 
Randomization will occur in equal proportions using stratified blocked randomization 
with first treatment as a stratifying variable. 
“Non-responders” will continue Stage 1 pharmacotherapy (NB/placebo) and 
50% will be randomized to receive CBT (weekly for 8 weeks and biweekly for 8 weeks) 
in addition to continued pharmacotherapy. Participants and researchers will remain 
blind to pharmacotherapy condition. 
 “Non-responders” to Stage 1 who were not randomized to CBT in Stage 2 will be 
given the option of receiving CBT after Stage 2 post has been completed and before 
entering the follow-up stage. Participants who choose to receive CBT after Stage 2 will 
have an additional post-treatment assessment when they finish CBT treatment, and 
then will begin the follow-up stage. 
The study biostatistician (Dr. Gueorguieva) will create randomization lists and 
communicate directly with the research pharmacist.
Stage 2 Treatment Protocols:
Treatment Protocol for Naltrexone/Bupropion (NB) Pharmacotherapy: Medication 
prescription and dosage will be the same as described in the NB Treatment protocol for 
Stage 1. Participants will meet with the study physician for a brief visit at the start of 
Stage 2, and will meet with study staff monthly throughout Stage 2 treatment.
“Responder” participants randomly assigned to discontinue medication will 
receive a one-week down-titration followed by placebo. Participants randomly assigned 
to continue active medication will receive the same active dose throughout Stage 2. 
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Participants randomly assigned to begin NB medication in Stage 2 will receive a three-
week dose escalation as previously described. The double-blind will be maintained by 
providing all participants with three weeks of medication in dated envelopes. 
“Non-responder” participants will continue their Stage 1 NB/placebo 
pharmacotherapy without interruption.
After 12-month follow-up assessments are completed, patients will be informed 
(separately from investigators by research pharmacist) whether they were on NB or 
placebo. Medication double-blind will be maintained for investigators and outcome 
assessors until all participants have completed final 12-month follow-up assessments. 
Treatment Protocol for CBT: In Stage 2 treatment, “non-responders” to Stage 1 
treatments will be randomly assigned to receive CBT or not. CBT will be delivered by 
research-clinicians based on CBT treatment manuals (Fairburn, Marcus, & Wilson, 
1993) used in our previous RCTs (Grilo, Masheb, & Salant, 2005; Grilo et al., 2011) and 
similar to those used in leading CBT RCTs (Wilfley et al., 2002). CBT manuals provide 
detailed session-by-session procedures for the clinicians and patients. CBT is a 
“specialist” focal treatment with three overlapping phases. (1) Establishing a 
collaborative therapeutic relationship while focusing on educating patients about the 
nature of binge eating and factors thought to maintain the problem. Specific behavioral 
strategies (e.g., self-monitoring) are used to help patients identify problematic eating 
behaviors while establishing a normal structured eating pattern. (2) Integrating cognitive 
restructuring procedures, focusing on helping patients learn to identify and challenge 
maladaptive cognitions regarding eating and weight/shape and thoughts that trigger 
binge eating. (3) Maintaining change and preventing relapse.
Stage 2 Post Assessment and Follow-up Assessments: After completing Stage 2 
treatment (NB, Placebo, CBT+NB, or CBT+Placebo), participants will complete one 
interview, the EDE. Other measures are described in the “Measures” grid that depicts 
when each measure is administered (page 15). 
Measures:
Figure 3. Grid depicting when each measurement is obtained
STAGE 1
STAGE 2
FOLLOW-UP
BASELINE 
ASSESSMENT
MID-TREATMENT 
WEEK 4
MID-TREATMENT 
WEEK 8
MID-TREATMENT 
WEEK 12
STAGE 1 ASSESSMENT 
(WEEK 16)
MID-TREATMENT 
WEEK 4
MID-TREATMENT 
WEEK 8
MID-TREATMENT 
WEEK 12
STAGE 2 ASSESSMENT 
(WEEK 16)
6 MONTH FOLLOW-UP
12 MONTH FOLLOW-UP
Clinical Interview:
EDE Interview
*
*
*
*
*
Medical history, Start of new 
treatments
*
*
*
*
MINI Psychiatric Interview
*
Self-report Questionnaires:
EDE-Q; Godin; BDI-II
*
*
*
*
*
*
*
*
*
*
*
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TFEQ; FCI-II; PFS
*
*
*
*
*
*
YFAS, ELOCS; PPAQ; SF-12
*
*
*
*
PSQI; Audit-2; UPPS
*
*
*
Physical Assessment:
BMI, BP, HR
*
*
*
*
*
*
*
*
*
*
*
Liver Function
*
*
*
*
Lipids, GC
*
*
*
*
Opiate drug testing
*
As needed: Pregnancy testing
*
As needed: TSH
*
Perceptions of Treatment:
Treatment Credibility
*
*
*
Compliance, Adverse Events
*
*
*
*
*
*
*
*
Placebo Rating
*
*
*
*
Treatment Satisfaction
*
*
Clinical Interviews: 

MINI International Neuropsychiatric Interview-Version 7.0 (MINI) (Sheehan et al., 
1998) is a brief structured interview for Axis I psychiatric disorders. Validation 
and reliability studies have supported the MINI, including good convergence with 
SCID (Sheehan et al., 1998). 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) (Fairburn & Cooper, 
1993) 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 (Grilo, Masheb, & Wilson, 2001b), is the major 
outcome measure for BED RCTs (Wilfley et al., 2002; Wilson et al., 2010), and 
has good test-retest reliability.

We will also gather clinical data on the patient’s medical history prior to the study, 
which we will update as indicated in Figure 1. If patients begin other treatments, 
this will allow us to account for this in analyses.
Assessment Training: Independent outcomes assessors will receive training in 
diagnostic interviews from investigators following well-established protocols used in 
previous projects. Once interviewers are certified in the measures (MINI and EDE), they 
will receive ongoing supervision to ensure consistent use and prevent drift. 
Self-Report Questionnaires:

Eating Disorder Examination-Questionnaire Version (EDE-Q). The self-report 
EDE-Q (Fairburn & Beglin, 1994) generates the same overeating data and scale 
scores as the EDE interview. EDE-Q has good test-retest reliability with BED 
patients (Grilo, Masheb, & Wilson, 2001a; Grilo et al., 2001b; Reas, Grilo, & 
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Masheb, 2006). The EDE-Q converges well with the EDE as a measure of 
“change” (Sysko, Walsh, & Fairburn, 2005). 

Godin Leisure Time Exercise Questionnaire (Godin) (Godin & Shephard, 1985) 
assesses frequency of mild, moderate, and vigorous physical activity. The Godin 
has good test-retest reliability (Godin & Shephard, 1985) and has good support 
from validation studies using various activity measurements such as activity 
monitors and maximum oxygen consumption (Miller, Freedson, & Kline, 1994).

Beck Depression Inventory (BDI-II). The BDI (Beck & Steer, 1987) 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 (Beck, Steer, & Carbin, 1988). 

Three Factor Eating Questionnaire (TFEQ) (Stunkard & Messick, 1985) 
measures eating behaviors with 3 factors: cognitive restraint, disinhibition, and 
hunger. TFEQ has empirical support (Foster et al., 1998), and shows differential 
response across treatments consistent with putative mechanisms (Grilo & 
Masheb, 2005; Safer, Agras, Lowe, & Bryson, 2004). 

Food Craving Inventory (FCI-II) (White, Whisenhunt, Williamson, Greenway, & 
Netemeyer, 2002) 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 
(White & Grilo, 2005; White et al., 2002). 

Power of Food Scale (PFS) (Lowe et al., 2009) 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 (Cappelleri et al., 2009). 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) 
(Cappelleri et al., 2009). 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 (Rejeski et al., 2012). 

Yale Food Addiction Scale (YFAS) (Gearhardt, Corbin, & Brownell, 2009) 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.

Eating Loss of Control Scale (ELOCS) (Blomquist et al., 2014) 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 obese persons with BED.

Paffenbarger Physical Activity Questionnaire (PPAQ) (Paffenbarger, Hyde, Wing, 
& Hsieh, 1986) measures specific physical activity (complementing the Godin) 
and has been used extensively in epidemiological (Paffenbarger, Hyde, Jung, & 
Wing, 1984; Paffenbarger, Wing, & Hyde, 1978) and obesity treatment studies. 
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PPAQ has good psychometrics (Albanes, Conway, Taylor, Moe, & Judd, 1990) 
and correlates significantly with expensive and burdensome fitness measures 
(Siconolfi, Lasater, Snow, & Carleton, 1985).

Medical Outcomes Study Short-Form Health Survey (SF-12) (Ware & 
Sherbourne, 1992) is widely-used measure of health related quality of life. This 
measure has well-established reliability and validity (McHorney, Ware, Lu, & 
Sherbourne, 1994; McHorney, Ware, & Raczek, 1993) for physical health and 
mental health domains. 

Pittsburg Sleep Quality Index (PSQI) (Buysse, Reynolds, Monk, Berman, & 
Kupfer, 1989) 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) (Bohn, Babor, & Kranzler, 
1995) is a measure that assesses alcohol use. The AUDIT has been used 
extensively and demonstrates high internal consistency and good test-retest 
reliability (Reinert & Allen, 2007). 

UPPS-P Impulsivity Scale (UPPS) (Whiteside & Lynam, 2001) measures 
impulsivity in five domains: negative urgency (acting rashly in response to 
negative emotions), positive urgency (acting rashly in response to positive 
emotions), lack of premeditation (acting without taking into account 
consequences), lack of perseverance (difficult remaining focused on difficult or 
boring tasks), and sensation-seeking (favoring stimulating or exciting activities) 
(Cyders, Littlefield, Coffey, & Karyadi, 2014).
Physical Assessment:

Lipid profiles (Lipids): total cholesterol, HDL-, LDL-cholesterol, triglycerides will 
be obtained fasting per established protocols (Anderson et al., 1995). 

Glycemic Control (GC): 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. 

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 assessed for all patients. 

Pregnancy testing will be assessed for female patients of child-bearing potential.

Body Mass Index (BMI) will be calculated using measured Height (measured 
once at baseline) and Weight (obtained regularly at assessment meetings).

Blood Pressure (BP) and Heart Rate (HR). BP readings (both systolic and 
diastolic) and HR will be obtained regularly at assessment meetings.
Perceptions of Treatment:

Treatment Credibility and Satisfaction. Credibility and Satisfaction ratings will 
allow patients to provide feedback on the treatment and treatment delivery. 
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
Treatment Compliance will include pill count method for medication treatment 
and session attendance as compliance measure for BWL. 

Adverse Events will be assessed using an adverse event checklist of most 
commonly reported adverse events for NB. Research-clinicians will ask open-
ended and follow-up questions as needed. 

Placebo Ratings. Patients and clinicians will record whether they believe the 
patient is on active medication or placebo. 
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.
D. Genetic Testing  N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will 
be received
iii. the types of information about the donor/individual contributors that will be 
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
E. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
One hundred sixty (N=160) participants with obesity and binge-eating disorder, and 
meeting other eligibility criteria as described below, will be randomized to participate 
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in this trial. Previous work with this population suggests participants will be adults, 
male and female, and represent diverse racial/ethnic and sociodemographic groups. 
F. 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.
 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 (If yes, see Instructions section VII #4 for further 
requirements)
G. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or  
exclusion?
Participants will be recruited using the same broad advertisements as in our 
previous RCTs (see page 36). Potential participants will be screened by telephone 
(or, if preferred by the participant, through the Yale Qualtrics system) and potentially 
eligible patients will be consented and evaluated in-person by trained doctoral 
clinicians.
Inclusion Criteria:
(1)
18 to 70 years old;
(2)
Meet DSM-5 criteria for BED based on semi-structured diagnostic interview 
(EDE);
(3)
BMI 27-30 with a controlled obesity-related co-morbidity; or BMI ≥ 30 and <50; 
(4)
Available for the duration of the treatment and follow-up (20 months).
(5)
Read, comprehend, and write English at a sufficient level to complete study-
related materials.
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)
Currently taking MAOI medication, or history of hypersensitivity.
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(4)
Currently taking opioid pain medications or drugs.
(5)
Positive urine drug screen for opiates.
(6)
Currently using effective medications for weight loss.
(7)
History of allergy or sensitivity to bupropion or naltrexone.
(8)
Co-existing psychiatric condition that requires hospitalization or more intensive 
treatment (e.g., bipolar mood disorders, psychotic illnesses, severe 
depression).
(9)
Untreated hypertension with a seated systolic blood pressure > 160 mmHg, 
diastolic blood pressure > 100 mmHg, or heart rate > 100 beats/minute.
(10) History of congenital heart disease, cardiovascular disease, cardiac 
arrhythmias requiring medication, atherosclerotic disease, or a history of 
cerebrovascular pathology including stroke.
(11) Current uncontrolled Type I or Type II diabetes mellitus.
(12) Untreated hypothyroidism with a TSH > 1.5 times the upper limit of normal for 
the test laboratory.
(13) Gallbladder disease.
(14) History of severe renal, hepatic, neurological, chronic pulmonary disease, or 
any other serious, unstable medical disorder.
(15) Current or recent (within 12 months) drug or alcohol dependence 
(16) Currently receiving effective treatment for eating or weight loss. 
(17) 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.
(18) Breast-feeding or pregnant, or not using a reliable form of birth control. 
(19) Reports active suicidal or homicidal ideation. 
H. How will eligibility be determined, and by whom? 
Diagnostic Assessment. Participants will be interviewed by trained and supervised 
doctoral-level research-clinicians (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.
Physical Assessment. The study physician will determine medical eligibility based 
on results of participants’ physical examination (within one year of starting the 
study), and/or approval of participant’s primary care provider, as well as results of 
the baseline assessment. Information obtained from the physical examination will 
include a list of current medications, which participants will be asked to bring to their 
baseline assessment.
I.
Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
NB Pharmacotherapy. 
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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. 
Participants will have a 50% chance (by random) of receiving placebo instead of NB 
during Stage 1. Since participants have a 50% chance of receiving BWL at the first 
stage of treatment, there is a 25% chance (by random) overall of receiving only 
placebo. Since participants have a 50% of receiving CBT in the second stage (if they 
are non-responders), the chances of receiving only placebo drop to roughly 12.5%. 
Additionally, “non-responders” to Stage 1 who were not randomized to CBT in Stage 
2 will be given the option of receiving CBT after Stage 2 post has been completed.
Assessments, Interviews, and Behavioral Treatment. 
BWL is an established and widely-used standard obesity treatment. CBT is an 
established “specialist” treatment for BED (considered the leading treatment by 
various research guidelines). Neither BWL nor CBT have any meaningful risks. With 
BWL, the only foreseeable risks include some mild discomfort or embarrassment 
when discussing eating patterns and weight. Some mild hunger may be experienced 
initially when attempting to follow the modest caloric guidelines. Some mild fatigue 
may be experienced initially when attempting to increase modest lifestyle physical 
activity. With CBT, the only foreseeable risks include some mild discomfort or 
embarrassment when discussing binge eating, body image, and associated thoughts 
and feelings. Previous controlled clinical trials with similar interventions with large 
numbers of similar patients have not reported problems. Any troublesome effects 
would be readily identifiable by the experienced research clinicians during the 
repeated evaluations. 
Research assessments are all noninvasive, and should add no substantial risk. The 
major disadvantages are the time taken to complete them and possible breach of 
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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. Subsequently, participants 
will be identified only by that number and an encoded version of their initials (e.g., 
John Smith = JSMI). 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 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.
J.
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. Participants 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 will be asked to have a pregnancy test, 2) 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 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. 
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 
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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.
Warning about Opioid Withdrawal: We will include this advisory pertaining to opioid 
use and examples of opioid-based medications and drugs in the written consent 
form, verbal consent process, and on the wallet card: 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. 
Urine drug screen for opiates: Participants will be asked to have a urine drug screen 
for opiates. Participants with a true positive test for opiates will be excluded, per 
exclusion criteria. 
Monitoring of Depressive Symptoms. To monitor changes in depressive symptoms, 
patients will be asked to complete the BDI-II at monthly clinic visits. Research 
clinicians will review BDIs during the clinic visit, and if indicated, will asked pointed 
questions pertaining to suicidality. If the research clinician judges that the participant 
is experiencing significant adverse effects of the medication, the investigators and 
study physician will be consulted to determine whether to discontinue the 
medication. The participant will be compensated in full, and will be asked to continue 
to attend clinic visits and to continue to participate (if applicable) in the BWL/CBT 
treatment to ensure remission of any distressing symptoms. If warranted, the 
participant will be given a referral. In addition, the following advisory will be included 
in the verbal consent process, and written on the consent form: The U.S. Food and 
Drug Administration (FDA) has issued an Advisory cautioning health care providers, 
patients, and families to closely watch individuals taking naltrexone/bupropion 
medication for signs of their depression getting worse and for thoughts of killing or 
harming themselves, especially during the first several weeks that the medication is 
being taken. Patients and their families should watch for and promptly report new 
symptoms. For example, report to the study doctor as soon as possible any signs of 
impulsivity (taking action or saying something without thinking first), agitation (feeling 
nervous or finding sitting still very difficult), and panic attacks (extreme fear without 
apparent reason).
Blood pressure and heart rate will be measured during all evaluation visits. Two 
readings will be taken at each assessment. In the event of high systolic blood 
pressure, diastolic blood pressure, or heart rate, the study physician will be notified 
and will determine whether additional intervention and/or medication discontinuation 
is warranted. 
Liver function will be measured during baseline and month-1 clinic visits of Stage 1 
and Stage 2. The study physician will review results. Participants with hepatic 
disease will be excluded if this is detected at baseline, per exclusion criteria. The 
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study physician will determine whether changes or out-of-range values require 
additional intervention and/or medication discontinuation.
Medication Titration. Participants will have a three-week dose escalation as 
previously described: one tablet daily (Naltrexone 8mg/ Bupropion 90mg; 1 week), 
two tablets daily (Naltrexone 16mg/ Bupropion 180mg; 1 week), three tablets daily 
(Naltrexone 24mg/ Bupropion 270mg; 1 week), followed by the full dose for the 
remainder of treatment. 
If participants drop out of the study during either treatment phase, 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.
 
K. 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.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
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://www.yale.edu/hrpp/forms-templates/biomedical.html for
i. Minimal risk
ii. Greater than minimal
d. For multi-site studies for which the Yale PI serves as the lead investigator: 
 N/A
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
The principal investigator will be responsible for monitoring the data, assuring 
protocol compliance, and conducting the safety reviews monthly. During the review 
process, the principal investigator will evaluate whether the study should continue 
unchanged, require modification/amendment, or close to enrollment. Either the principal 
investigator, the IRB, the study physician or the research safety monitor (Cenk Tek, MD) 
has the authority to stop or suspend the study or require modifications.
The risks associated with the current study are deemed greater than minimal for 
the following reasons: 
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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.
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 or in advance of first-hand experience with the proposed study 
methods. Therefore, we provide a plan for monitoring the data and safety of the 
proposed study as follows:
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s).
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 
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 requiring in-patient hospitalization or prolongation 
of existing hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the participant’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition. 
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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.
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1. Is unexpected (in terms of 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 participant population being studied; AND 
2. Is 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 (including physical, psychological, economic, legal, or social harm) than 
was 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. 
Please note that 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. 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. 
For the current study, the following individuals, funding, and/or regulatory agencies will 
be notified (choose those that apply):
X All Co-Investigators listed on the protocol, including the study physician and the 
protocol’s research safety monitor, Cenk Tek, MD.
□ Yale Cancer Center Data and Safety Monitoring Committee (DSMC)
□ National Institutes of Health
□ Food and Drug Administration (Physician-Sponsored IND #_______)
□ Medical Research Foundation (Grant______)
□ Study Sponsor
□ Other Data Safety Monitoring Board (DSMB) or Committee (DSMC)
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The principal investigator will evaluate the frequency and severity of the adverse events 
and determine if modifications to the protocol or consent form are required. The 
principal investigator will review all adverse events upon completion of every study 
subject.
L. 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 
adherence to normal distribution using normal probability plots and Kolmogorov-
Smirnov tests. If normality is not satisfied and transformations do not help with 
achieving normality, alternative analytic strategies will be considered such as 
generalized estimating equations or nonparametric methods. Dropouts and completers 
will also be compared. Analyses will be intent-to-treat. Primary outcomes will be tested 
at the two-sided 0.05 significance level. Secondary analyses will be adjusted for multiple 
tests using Bonferroni correction.
Overall analysis strategy: Mixed-effects models (Diggle, Heagerty, Liang, & Zeger, 
2002) will be used to compare treatments. These models allow for different numbers of 
observations per participant, use all available data on each participant, 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, we will include fixed effects of time, BWL, NB and all possible 
interactions, and random participant-level 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, independence) and select the best fitting one based 
on information criteria. 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 (Hedeker & Gibbons, 1997) to perform sensitivity analyses.
Stage 1 RCT – Primary Aim #1: Test effectiveness of BWL and NB medication, alone 
and in combination, for BED. The primary aims are to evaluate the effectiveness for (a) 
reducing binge eating and (b) reducing weight. In the mixed models, the dependent 
variables will be (a) reduction in binge eating frequency, and (b) Percent weight loss. In 
view of the factorial design we will also be able to assess whether there are interactive 
or additive effects of the two treatments. We do not have a priori hypothesis regarding 
the interaction but will test it together with the main effects.
Stage 1 RCT – Secondary Aims: (a) Explore effectiveness of BWL and NB 
medication, alone and in combination, on secondary outcomes: remission (zero binges 
past 28 days), eating-disorder pathology (EDE global), and depression (BDI). To 
compare remission rates across groups we will use logistic regression with BWL, NB 
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and the interaction as fixed effects. We will also test the interaction of the two 
treatments. Continuous secondary outcomes (EDE global and BDI) will be analyzed 
using the same approach as for primary aim 1. (b) Explore predictors, moderators, and 
mediators of primary outcomes (binge eating and weight loss). We will follow Kraemer’s 
(2002) conceptual/statistical models for exploring predictors, moderators and mediators 
for both binge eating and % weight loss outcomes. 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 physical activity (Godin, PPAQ) constructs 
relevant to BWL, food-reward constructs (FCI, PFS) relevant to putative mechanisms of 
action for NB, and depression (BDI) a conceptual/empirically-supported construct, will 
yield relevant change variables for analyses of mediation (i.e. testing subsequent 
changes in binge eating and weight).
Stage 2 RCT – Primary Aim # 2: Among responders to Stage 1 treatments, to evaluate 
the effectiveness for (a) binge eating and (b) weight. Our main hypothesis is that NB will 
have main effects on reduced binge eating and weight regains. In the mixed models for 
testing these hypotheses, the dependent variables will be (a) change in binge eating 
frequency and (b) percent weight change. 
Stage 2 RCT – Secondary Aims: (a) Among responders, explore effectiveness of NB 
medication vs. placebo on secondary outcomes: relapse to BED threshold (binge once 
weekly), eating-disorder pathology (EDE global), depression (BDI), social/medical 
functioning (SF-36), and metabolic function (Lipid, Hb1Ac). Relapse rates across groups 
will be compared with logistic regression with medication as a fixed effect. Continuous 
secondary outcomes (EDE global and BDI) will be analyzed using the same approach 
as for primary aim 1. (b) Explore whether Stage 1 treatment is a moderator of 
medication effects during Stage 2. To test this hypothesis we will include treatment 
during phase 1 and its interaction with medication in models above. We will estimate 
effect sizes for outcomes. 
Stage 2 RCT – Exploratory Aim: Among Non-responders to Stage 1, we will explore 
whether adding CBT enhances on-going pharmacotherapy (NB/placebo). We will 
compare CBT plus continued pharmacotherapy vs pharmacotherapy-only for reducing 
binge eating.
Power analysis: The sample size was based on the following power calculations.
Stage 1 RCT – Primary Aim #1: Reported effect sizes for naltrexone/bupropion effects 
on dimensional weight loss (% weight loss) are large (d=0.76 in Apovian et al (2013), 
d=0.98 in Greenway et al. (2013), and d=1.1 in Smith et al. (2013). However, because 
of the possibility of positive publication bias and since medium effect sizes (d=0.5) or 
larger are also considered clinically meaningful, we conservatively power our study to 
detect medium effect sizes. With 40 participants in each cell of the design table, we will 
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have at least 80% power to detect such effect sizes (d=0.5, f=0.25) for the medication 
main effects at 2-sided significance level of 0.05 even after accounting for 20% dropout. 
With the sample sizes per group we are also well powered (power > 80%) to detect 
clinically meaningful effect sizes (f=0.25) for the interaction test between BWL and NB 
on percent weight loss even after assuming 20% dropout. Dropout rate is based on 
completion rates for our earlier RCTs with BED (87% in Grilo & Masheb, 2005; 84% in 
Grilo, White et al., 2014). 
Stage 1 RCT – Secondary Aims: Remission rates for BWL for BED from our previous 
RCTs were 50% (Grilo & White, 2013) and 74%; Wilson, Wilfley et al. (2010) reported 
55% remission rate for BWL for BED. Thus, we conservatively calculate power based 
on estimated 50% remission rate for BWL alone. Remission rates for no-BWL/placebo 
are estimated at 10-15% (based on McElroy (2015) placebo rates in 2 large RCTs of 
14% and 13%). We estimated remission rate for NB medication at 45% (synergistic 
action of NB medication expected to produce higher rate than the 42% rate for 
bupropion-only (White & Grilo, 2013) and expect higher remission rate for the 
combination BWL/NB of 60%-70%. This results in the following projected effect sizes for 
the main effects of BWL (55% vs 28%, 60% vs 30%) and NB (53% vs 30%, 58% vs 
33%). With sample size of 40 in each cell, we have more than 80% power to detect 
such differences assuming 2-tailed tests, alpha=0.05, with 20% dropout. 
Stage 2 RCT: Based on our previous RCTs, we anticipate 70% of participants on 
BWL+NB and 65% on BWL or on NB will be responders. This yields a sample size of 88 
participants (28 on BWL+NB, 26 on BWL, 26 on NB, and 8 on placebo) for 
randomization to Stage 2 NB or placebo. Thus, if we base power calculation for phase 2 
on 44 participants per group and account for 20% dropout, we have at least 80% power 
to detect a medium to large effect size (d=0.68) for the difference between NB vs 
placebo at 2-tailed alpha of 0.05. For relapse, we can detect the following clinically 
meaningful differences in proportions (15% vs 45%, 30% vs 63%, 45% vs 77%) at 2-
tailed alpha of 0.05.
Stage 2 RCT – Exploratory Aim: With N=72 non-responders (N=36 assigned to 
continuing medication (NB/placebo) and N=36 assigned to CBT plus continuing 
medication (NB/placebo), we would have 80% power to detect d=0.75 (remission rates 
of 5% vs 32%, 15% vs 49%, 30% vs 66%) at 2-tailed alpha level of 0.05 assuming up to 
20% dropout.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A. DRUGS, BIOLOGICS and RADIOTRACERS 
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1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the 
drug(s) biologic(s) or radiotracer(s) being used? Identify whether FDA approval has been 
granted and for what indication(s). 
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).
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated 
by, the FDA, or a radiotracer regulated by the RDRC, must provide the following 
information: 
 N/A
a. What is the Investigational New Drug (IND) number assigned by the FDA?
b. Who holds the IND? 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA 
must provide the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: 
(check if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp. When you have logged in, 
complete the application and attach a copy to this submission.   
Alternatively, an exemption from IND filing requirements may be sought for a clinical
investigation of a drug product that is lawfully marketed in the United States. If there is 
no IND and an exemption is being sought, 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:
i.  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. 
 Yes 
 No
ii. 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. 
 Yes 
 No
iii. 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. 
 Yes 
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)  
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   review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 
21 CFR Part 56). 
 Yes 
 No
v.  The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes 
 No
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. 
NB Pharmacotherapy. An FDA-approved anti-obesity pharmacotherapy 
approach involves the combination of naltrexone and bupropion which has received 
empirical support in several RCTs performed with obesity (non-BED). 
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 (O'Malley et al., 
2007). Naltrexone produces weight loss in lab animals but only minimal weight 
losses in people (Billes & Greenway, 2011; Malcolm et al., 1985). Bupropion 
operates through dopaminergic, noradrenergic, and nicotinic acetyl-cholinergic 
mechanisms (Han, Hwang, & Renshaw, 2010; Slemmer, Martin, & Damaj, 2000; 
Stahl et al., 2004). Bupropion may target reward processes that drive eating 
behaviors, consistent with its FDA indication for treating nicotine dependence and 
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reduced weight gain during smoking cessation (Farley, Hajek, Lycett, & Aveyard, 
2012; Hurt et al., 1997). Bupropion promotes weight loss (Li et al., 2005): 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 
(2013) reported preliminary, modest support for weight loss specifically in patients 
with obesity and BED.
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 (Billes & Greenway, 2011). The anorectic effects of 
leptin result from its excitatory effects on pro-opiomelanocorin (POMC) neurons in 
the hypothalamus melancortin system (Cowley et al., 2001; Marsh et al., 1999). 
Stimulated POMC signaling decreases food intake, increases energy expenditure, 
but is then inhibited by endogenous feedback (Cowley et al., 2001). Thus, combining 
these two drugs will stimulate POMC neurons (bupropion) plus block endogenous 
feedback that inhibits POMC activity (naltrexone) (Billes & Greenway, 2011; 
Greenway, Whitehouse, et al., 2009). This synergistic model received support both 
in vitro and in vivo studies (Cone et al., 2001; Greenway, Whitehouse, et al., 2009).
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 (Greenway et al., 2010; Greenway, 
Whitehouse, et al., 2009; Smith et al., 2013; Wadden et al., 2011). 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 et al. (2013), 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% (Smith et al., 2013); 52% vs. 15% (Greenway, 
Dunayevich, et al., 2009). 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 (Greenway et al., 2010; Greenway, 
Whitehouse, et al., 2009; Smith et al., 2013; Wadden et al., 2011). 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 
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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: a) Identify the source of the drug or biologic to be used. 
NB will be purchased using funds awarded in this grant. 
b) Is the drug provided free of charge to subjects? 
 Yes 
 No
  If yes, by whom? 
4. 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. 
Check applicable Investigational Drug Service utilized:
   
  YNHH IDS                                   
  Yale Cancer Center 
   
  CMHC Pharmacy                             
 West Haven VA
   
  PET Center                           
  None   
   
  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. 
 
5. 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 (Wilson et al., 2007) and critical quantitative meta-analytic reviews 
(National Institutes of Clinical Excellence, 2004) 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 (Reas & Grilo, 2008, 2014). 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 
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loss ranging from modest to none (Reas & Grilo, 2008). Placebo-controlled trials of 
anticonvulsants topiramate and zonisamide (Claudino et al., 2007; McElroy et al., 
2003; McElroy et al., 2006) 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 (McElroy et al., 2004). SSRI 
antidepressants, previously regarded as a potential treatment strategy (National 
Institutes of Clinical Excellence, 2004) are characterized by small effect sizes 
relative to placebo (Reas & Grilo, 2008) and produce no weight loss at all (Grilo, 
Masheb, & Salant, 2005) and are inferior to CBT (Grilo, Masheb, & Wilson, 2005; 
Ricca et al., 2001). There are currently no FDA-approved medications for BED.
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 8 months if randomized to 
placebo during both Stage 1 and Stage 2 of this study 
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 (Reas & Grilo, 2014).
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 (Reas & Grilo, 2014). 
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 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. 
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes 
 No See HIC Application Instructions to view controlled substance listings. 
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If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
7. 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. 
 
 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
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
targeted for enrollment at Yale for this protocol N=160
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
Posters   
Letter   
Medical Record Review  
Departmental/Center 
Newsletters 
YCCI Recruitment database 
Other (describe): EPIC direct to 
patient
Internet/Web Postings  
Mass E-mail Solicitation  
Departmental/Center Website 
Departmental/Center Research 
Boards 
Web-Based Clinical Trial 
Registries 
Clinicaltrials.gov Registry (do 
not send materials to HIC)
Radio
Telephone
Television
Newspaper
 Billboards
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 
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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). 
EPIC Direct to Patient MyChart confidential messaging will be utilized for 
recruitment of subjects meeting specific parameters (Adults meeting weight 
inclusion criteria who are not on anti-depressant medication, using other 
exclusion criteria to refine sample to those likely eligible).  The following 
template will be utilized:
Title of study, Phase or type of study:  Behavioral and Pharmacologic 
Treatment of Binge Eating and Obesity
Principal Investigator:  Carlos Grilo, Ph.D.
Study Contact:  Janet Lydecker, Ph.D.     Phone #  203-785-7210
Description:    
If you are 18 to 70 years old with binge-eating disorder and obesity, and are 
not taking anti-depressant medications, you may be eligible to participate in a 
free and confidential study that may help with long-lasting weight loss. No 
cost treatment provided (FDA-approved medication, behavioral, or both). 
Participants will receive up to $400 compensation. To learn more or see if you 
are eligible to participate, please call the Yale Program for Obesity, Weight, 
and Eating Research at: (203) 785-7210 or visit 
http://psychiatry.yale.edu/research/programs/clinical_people/power.aspx. 
Please indicate how often you would like to receive new names of potential 
participants    ☐    daily    ☒ weekly
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 and/or respond to an 
online form, 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 
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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 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. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes 
 No
b.
 If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process. 
HEALTH INFORMATION TO BE COLLECTED:
 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, 
zip codes and their equivalent geocodes, except for the initial three digits of a zip code if, according to 
the current publicly-available data from the Bureau of the Census: (1) the geographic unit formed by 
combining all zip codes with the same three initial digits contains more than 20,000 people, and (2) the 
initial three digits of a zip code for all such geographic units containing 20,000 or fewer people is 
changed to 000. 
 Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
 All elements of dates (except year) for dates related to an individual, including: birth date, 
admission date, discharge date, date of death, all ages over 89 and all elements of dates (including 
year) indicative of such age, except that such ages and elements may be aggregated into a single 
category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
5. 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? 
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 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
6. 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 purposes only
☐ For inclusion of non-English speaking subject if short form is being used
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
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;
Participants will initially call us and/or fill out an online interest 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. 
By signing this protocol application, 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.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
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8. Consent Personnel: List the names of all members of the research team who will be 
obtaining consent/assent. 
List of Investigators / Study Personnel:
Person Name
Department
Lead 
Unit Role
Consenting
Grilo, Carlos M
 MPSY O S A Y P I
Principal Investigator
Yes
Barnes, Rachel
Personnel
Yes
Bartel, Maya
Study Personnel
Yes
Cooper, Zafra
Personnel
No
Gueorguieva, Ralitza
Personnel
No
Ivezaj, Valentina
Personnel
Yes
Leiner, Emily Isadora
Personnel
Yes
Lydecker, Janet
Personnel
Yes
Massoumi, Mehran M
Personnel
Yes
Morgan, Peter Thomas
Personnel
Yes
O'Brien, Elizabeth
Study Personnel
No
Rasmusson, Grace Elizabeth
Study Personnel
Yes
Tsopelas, Lindsay Mariel
Study Personnel
Yes
Wang, Shirley
Study Personnel
No
Warren, Justine Ilia
Personnel
Yes
White, Marney A.
Personnel
No
9. 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. 
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. 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.
10. 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. 
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the 
same format that they will be given to subjects. 
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The Compound Authorization Form is attached.
12. 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
12(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 found on our website at: 
http://www.yale.edu/hrpp/forms-templates/biomedical.html. 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 amendment 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. 
13. 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 a consent waiver 
 
 Requesting a waiver of signed consent
 
 Requesting a full waiver of consent
  
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the 
research? 
 Yes 
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes 
 No
OR
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c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes 
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an 
information sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the 
research? 
 Yes 
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes 
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, 
stop. A waiver cannot be granted.  
 No 
AND
d. Does the research include any activities that would require signed consent in a 
non-research context? 
 Yes 
 No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects? 
 Yes If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes 
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects? 
 Yes If you answered yes, stop. A waiver cannot be granted. 
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 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes 
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
a.
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.
Lab results (bloodwork and urine tests), including urine drug screen for opiates, 
will be collected and used for research.
    
b. 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 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. 
Information about positive urine drug screens, should they occur, will be recorded 
using the participant study number. Results from drug screens that are 
conducted alongside bloodwork and therefore have identifiable data will be 
retained for the duration of the study and maintained on secure Yale servers (for 
electronic data) or in locked research cabinets within a locked suite. We will 
destroy positive urine drug test results that occur alongside identifiable 
information as soon as the participants is determined to be ineligible. 
c.
How will the digital data be stored? 
 CD 
 DVD 
 Flash Drive 
 Portable Hard  
    Drive 
 Secured Server 
 Laptop Computer 
 Desktop Computer 
 Other
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d. 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?
Do all portable devices contain encryption software? 
 Yes  
 No 
 N/A
     If no, see http://hipaa.yale.edu/guidance/policy.html
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.
e.
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. 
f.
Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and 
de-identified data) 
The PI and research staff will have access to the PHI. 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 participants, 
including the Yale Human Investigation Committee (HIC), 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 Insurance Portability 
and Accountability Act of 1996.
g. If appropriate, has a Certificate of Confidentiality been obtained? 
 N/A
h. Are any of the study procedures likely to yield information subject to mandatory reporting  
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will 
need to be reported. 
No, this is unlikely.
SECTION IX: POTENTIAL BENEFITS
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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.
     SECTION X: 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. 
STAGE 1
STAGE 2
FOLLOW-UP
BASELINE 
ASSESSMENT
MID-TREATMENT 
WEEK 4
MID-TREATMENT 
WEEK 8
MID-TREATMENT 
WEEK 12
STAGE 1 ASSESSMENT 
(WEEK 16)
MID-TREATMENT 
WEEK 4
MID-TREATMENT 
WEEK 8
MID-TREATMENT 
WEEK 12
STAGE 2 ASSESSMENT 
(WEEK 16)
6 MONTH FOLLOW-UP
12 MONTH FOLLOW-UP
Payment for Participation
$20
$100
$100*
$80
$100
Participants will be reimbursed when they complete the assessments at baseline 
($20), and at the end of Stage 1 ($100), Stage 2 ($100), 6-Month Follow-up ($80), 
and 12-Month Follow-up ($100). At baseline, conditions for receiving compensation 
include attending the appointment. At subsequent assessments, conditions for 
receiving compensation include completion of surveys, bloodwork, and interview. 
*A minority of patients (estimated to be 5% of all participants) will have the option to 
receive CBT after Stage 2 before completing follow-up assessments (See page 
Randomization to Stage 2 Treatments:
14). These patients will be asked to complete an additional assessment (prior to the 
follow-up stage) and will therefore receive an additional $100 at the time of that 
assessment. Conditions for receiving compensation include completion of interview, 
surveys, and bloodwork.
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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.) 
4. In Case of Injury: This section is required for any research involving more than minimal 
risk.
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. 
e.
How will the medical treatment be accessed by subjects? 
Referrals will be provided.
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