A Behavioral Treatment With Sequenced Adjunctive Pharmacotherapy for Weight Regain After Bariatric Surgery: A Pilot Study
Phase: PHASE2
Conditions: Obesity, Overweight
Sponsor: Yale University

ClinicalTrials.gov ID: NCT04662801 
Title: Weight Regain Treatment Post-Bariatric Surgery 
Date: 11/30/2021 
Document: Protocol w SAP 

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CLINICAL STUDY PROTOCOL
A Behavioral Treatment with Sequenced Adjunctive 
Pharmacotherapy for Weight Regain After Bariatric 
Surgery: A Pilot Study
Protocol Number
2000029491
Principal Investigator
Valentina Ivezaj
Sponsor
American Psychological Foundation
Protocol Version
November 16, 2021
Confidentiality Statement:
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Study Personnel
Principal Investigator
Valentina Ivezaj
Email: valentina.ivezaj@yale.edu
 
Investigator
Carlos M Grilo
Email: carlos.grilo@yale.edu
 
Medical Monitor
Jorge Moreno
Email: jorge.moreno@yale.edu
 
Key Study Personnel:
Ashley Wiedemann
Email: ashley.wiedemann@yale.edu
 
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Synopsis
Primary Objective
This study aims to evaluate the feasibility and acceptability of adding a specific 
pharmacological treatment (Naltrexone+Bupropion combination [NB]) to behavioral 
treatment for non-responders among adults experiencing weight regain following 
metabolic and bariatric surgery (MBS). A behavioral treatment will be given to all subjects 
as the primary treatment. After one month of behavioral treatment, patients who do not 
show a "response" (based on weight-loss data) will begin a trial of a specific medication 
(in addition to continuing the behavioral therapy); repeated multi-modal assessments will 
assess whether the combined approach augments the behavioral therapy.
We hypothesize that the treatments will be feasible and acceptable to subjects, and that 
subjects will experience significant weight loss and improvements in psychosocial 
functioning. More specifically, it is hypothesized that early responders to BWL will show 
weight loss during the trial, while the addition of NB will aid early non-responders in 
achieving weight loss.
Secondary Objectives (if applicable)
This pilot will also examine whether augmenting behavioral treatment with NB results in 
improvements in psychosocial functioning.
Study Duration
Study duration will be three months.
Study Design
The proposed clinical trial will pilot the feasibility and acceptability of delivering behavioral 
weight loss treatment (BWL) to adults struggling with weight regain after MBS. All 
participants will receive BWL treatment. Early weight loss responders will continue with 
BWL for the duration of treatment, while early non-responders will be given NB as an 
adjunct to BWL. The pilot will also examine whether augmenting behavioral treatment with 
NB results in weight loss and improvements in psychosocial functioning.
Study Population
N=25 adults (aged 18-65) who experience weight regain after MBS will participate in the 
study. Weight regain will be defined by the recommended definition of weight regain in the 
field, that is, weight regain defined as the percentage of maximum weight lost ([100*(post-
nadir weight — nadir weight)]/(pre-surgery weight — nadir weight). Weight regain based 
on this definition was the best indicator of poor clinical outcomes.
Number of Participants
N=25
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Number of Study Sites
1
Primary Outcome Variables
Primary outcomes will include: 1) feasibility, 2) acceptability, and 3) weight loss.
1) Feasibility will be determined by examining enrollment, number of sessions attended, 
compliance, and retention.
2) Treatment credibility and satisfaction will be examined via self-report.
3) To examine weight changes, we will examine percent total weight loss for the entire 
participant group. We will also compare percent weight loss for the two responder groups. 
Secondary and Exploratory Outcome Variables (if applicable)
Secondary outcomes include changes in psychosocial functioning including eating-
disorder psychopathology, depressive symptoms, and food cravings.
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Abbreviations
Abbreviation 
Explanation
NB
Naltrexone+Bupropion 
MBS
Metabolic and Bariatric Surgery
RYGB
Roux-en-Y gastric bypass
LSG
Sleeve gastrectomy
BMI
Body Mass Index
BWL
Behavioral Weight Loss
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Table of Contents
Synopsis.....................................................................................................................................
Primary Objective ...................................................................................................................
Secondary Objectives (if applicable) ......................................................................................
Study Duration ........................................................................................................................
Study Design ..........................................................................................................................
Study Population.....................................................................................................................
Number of Participants ...........................................................................................................
Number of Study Sites............................................................................................................
Primary Outcome Variables....................................................................................................
Secondary and Exploratory Outcome Variables (if applicable) ..............................................
Visit Schedule Table (Optional) ..............................................................................................
Study Flow Chart (optional) ....................................................................................................
Abbreviations .............................................................................................................................
Glossary of Terms......................................................................................................................
1 - Introduction ...........................................................................................................................
1.1 Introductory Statement .....................................................................................................
2 - Background...........................................................................................................................
2.1.1 Preclinical Experience ...................................................................................................
2.1.2 Clinical Experience ........................................................................................................
2.2 Background/prevalence of research topic ........................................................................
3 - Rationale/Significance ..........................................................................................................
3.1 Problem Statement ...........................................................................................................
3.2 Purpose of Study/Potential Impact ...................................................................................
3.3.1 Potential Risks............................................................................................................
3.3.2 Potential Benefits........................................................................................................
4 - Study Objectives...................................................................................................................
4.1 Hypothesis ........................................................................................................................
4.2 Primary Objective .............................................................................................................
4.3 Secondary Objectives (if applicable) ................................................................................
5 - Study Design.........................................................................................................................
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5.1 General Design Description..............................................................................................
5.1.1 Study Date Range and Duration.................................................................................
5.1.2 Number of Study Sites................................................................................................
5.2 Outcome Variables ...........................................................................................................
5.2.1 Primary Outcome Variables........................................................................................
5.2.2 Secondary and Exploratory Outcome Variables (if applicable) ..................................
5.3 Study Population...............................................................................................................
5.3.1 Number of Participants...............................................................................................
5.3.2 Eligibility Criteria/Vulnerable Populations...................................................................
6 - Methods ................................................................................................................................
6.1 Treatment - Drug ..............................................................................................................
6.1.1 Identity of Investigational Product/New Drug..............................................................
6.1.2 Dosage, Admin, Schedule (if applicable)....................................................................
6.1.3 Method of Assignment/Randomization (if applicable)....................................................
6.1.4 Blinding and Procedures for Unblinding (if applicable)...............................................
6.1.5 Packaging/Labelling.......................................................................................................
6.1.6 Storage Conditions.....................................................................................................
6.1.7 Concomitant therapy......................................................................................................
6.1.8 Restrictions ....................................................................................................................
6.2 Assessments ....................................................................................................................
6.2.1 Efficacy ..........................................................................................................................
6.2.2 Safety/Pregnancy-related policy.................................................................................
6.2.2.1 Adverse Events Definition and Reporting................................................................
6.2.3 Pharmacokinetics (if applicable) ....................................................................................
6.2.4 Biomarkers (if applicable) ..............................................................................................
6.3 Study Procedures .............................................................................................................
6.3.1 Study Schedule..............................................................................................................
6.3.2 Informed Consent.......................................................................................................
6.3.3 Screening ...................................................................................................................
6.3.4 Recruitment, Enrollment and Retention......................................................................
6.3.5 On Study Visits ..............................................................................................................
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6.3.6 End of Study and Follow-up .......................................................................................
6.3.7 Removal of subjects ...................................................................................................
6.4 Statistical Method .............................................................................................................
6.4.1 Statistical Design........................................................................................................
6.4.2 Sample Size Considerations..........................................................................................
6.4.3 Planned Analyses ..........................................................................................................
6.4.3.1 Primary Analyses........................................................................................................
6.4.3.2 Secondary Objectives Analyses .................................................................................
6.4.3.3 Safety/Pregnancy-related policy .................................................................................
6.4.3.4 Analysis of Subject Characteristics.............................................................................
6.4.3.5 Interim Analysis (if applicable) ....................................................................................
6.4.3.6 Health economic evaluation........................................................................................
6.4.3.7 Other...........................................................................................................................
6.4.4 Subsets and Covariates.................................................................................................
6.4.5 Handling of Missing Data...............................................................................................
7 - Trial Administration ...............................................................................................................
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization...................
7.2 Institutional Review Board (IRB) Review ..........................................................................
7.3 Subject Confidentiality ......................................................................................................
7.4 Deviations/Unanticipated Problems..................................................................................
7.5 Data Collection .................................................................................................................
7.6 Data Quality Assurance ....................................................................................................
7.7 Study Records ..................................................................................................................
7.8 Access to Source..............................................................................................................
7.9 Data or Specimen Storage/Security .................................................................................
7.10 Retention of Records ......................................................................................................
7.11 Study Monitoring.............................................................................................................
7.12 Data Safety Monitoring Plan ...........................................................................................
7.13 Study Modification ..........................................................................................................
7.14 Study Discontinuation .....................................................................................................
7.15 Study Completion ...........................................................................................................
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7.16 Conflict of Interest Policy ................................................................................................
7.17 Funding Source ..............................................................................................................
7.18 Publication Plan ..............................................................................................................
Appendices ................................................................................................................................
List of Tables..............................................................................................................................
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1 - Introduction
1.1 Introductory Statement
Metabolic and bariatric surgery (MBS) is the most effective treatment for severe obesity and 
associated sequalae. Despite MBS' overall efficacy, weight regain with recurrence and/or 
onset of medical and psychological comorbidities is common and a matter of great concern. 
Very little is known about post-MBS treatments for weight regain. The goals of this proposal 
are to evaluate the feasibility and acceptability of evidence-based obesity treatments in post-
MBS patients. All eligible subjects who experience weight regain after MBS will be given 
behavioral treatment (BWL). After one month of BWL treatment, "treatment response" will be 
determined based on early weight loss status because of its strong prognostic significance 
for optimal weight loss outcomes. Early weight-loss responders will continue BWL treatment, 
while non-responders will be given a pharmacologic agent to augment BWL treatment. This 
study aims to explore whether the addition of specific pharmacotherapy to BWL amongst 
initial non-responders improves outcomes. The study will compare the two treatment 
conditions and will examine within-group weight and psychosocial changes over time in the 
combined treatment condition; these data will serve as pilot data and represent effect-size 
estimates to design and power larger definitive treatment trials testing combined behavioral 
and pharmacological interventions and stepped-care approaches to prevent weight regain 
after MBS.
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2 - Background
2.1 Background/prevalence of research topic
Individuals with obesity suffer from increased risk of cardiovascular morbidity and mortality, 
as well as type 2 diabetes, obstructive sleep apnea, dyslipidemias, asthma, and several 
cancers (1). Rates of obesity (defined as body mass index (BMI) ≥ 30) have steadily 
increased over the last few decades to a staggering 39.8% (2). Alarmingly, obesity 
prevalence in the general adult population is expected to rise to over 51%, with a 130% 
increase in severe obesity (BMI ≥ 40) by 2030 (3). These rates and projected future 
increases are deeply concerning given the substantial disease and economic burden of 
obesity (4). As severe obesity rates continue to rapidly rise, MBS is expected to increase. 
MBS is the most effective and enduring treatment for severe obesity and results in 
impressive acute and long-term weight loss and improvement and/or remission of medical 
comorbidities (5)and psychosocial sequalae (6). Currently, laparoscopic Roux-en-Y gastric 
bypass (RYGB) and sleeve gastrectomy (LSG) are the most commonly performed MBS 
procedures (7).   
Despite these impressive data, weight trajectories following both forms of MBS have 
significant variability. Data from the NIH-funded Longitudinal Assessment of Bariatric 
Surgery (LABS) consortium found substantial average weight loss by 3 and 7 years post-
RYGB, with most of the weight loss occurring during the first year post-surgery (8). 
Nonetheless, weight outcomes have marked heterogeneity in both RYGB and LSG. Lowest 
maximal weight loss was as low as -1.1% for LSG and -4.1% for RYGB, with ranges of 1.1-
58.3% for LSG and 4.1-60.9% for RYGB (9). Even for those with optimal outcomes, weight 
regain is not uncommon and there exists marked variability in weight losses achieved after 
MBS (9). Additionally, worsening or recurrence of medical and psychological comorbidities, 
is of great concern (10). 
Post-MBS Treatment is Needed.
Behavioral Treatment. Although the field recognizes the need for post-operative behavioral 
or psychosocial allied treatments, there is little guidance as to what should be provided 
based on empirical data. Of the limited research to date which has examined pre- and post-
MBS interventions to improve weight outcomes, results suggest that pre-surgical 
interventions have largely been ineffective at producing significant weight differences post-
surgically (11); however, behavioral treatments may have utility post-surgery (12).
Pharmacologic Treatment. Another promising, yet understudied, avenue involves the use 
of weight-loss medications after MBS. Emerging research suggests utility in weight-loss 
medications after MBS (13). The combination of Naltrexone and Bupropion (NB), also known 
as "Contrave," is an optimal starting point due to its consistent weight-loss evidence base, 
affordable costs, tolerable side-effects, safety profile, and putative mechanisms of action. In 
2014, the FDA approved NB for obesity following empirical support from several RCTs 
performed with obesity (14). These RCTs reported significant clinically-meaningful weight 
losses with naltrexone plus sustained-release bupropion combined in fixed-dose pills. These 
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findings supporting NB medication are consistent with large RCTs which reported greater 
weight loss with NB than placebo (-6.5 vs -1.2% (14)). Although the name brand (Contrave) 
is expensive, the combination of Naltrexone and Bupropion are available at affordable 
prices. Putative mechanisms of action for NB seem relevant for post-MBS patients who 
might also be struggling with maladaptive eating behaviors, such as loss-of-control (LOC) 
eating. LOC eating and related eating-disorder psychopathology are consistent predictors of 
poor outcomes after MBS (15). As reviewed in the preliminary data section below, NB may 
be helpful in both reducing problematic eating such as LOC eating (i.e., binge eating) and 
weight loss. Putative mechanisms of action for NB is especially relevant for reducing LOC 
eating and weight per hypothesized effects on brain regions implicated in the regulation of 
food intake and weight based on the mechanisms of action of leptin (16).
Early Weight Loss. Meaningful early weight loss, ranging from 0.5 to 3% weight loss during 
the first 1-2 months of treatment, is a consistent predictor of weight loss by the end of 
treatment and longer-term (17). Earlier work has found that at least 1% weight loss early in 
treatment was associated with meaningful weight loss at the end of treatment (17).
Collectively, the lack of evidence-based treatments after MBS remains a critical and 
concerning gap in the field. An evidence base is urgently needed to direct the field in 
managing obesity after surgical intervention. Given that BWL and NB are both empirically-
based weight-loss treatments, the proposed study will pilot the feasibility and acceptability of 
delivering behavioral treatment (BWL) to adults struggling with weight regain after MBS. 
Early weight loss responders will continue with BWL for the duration of treatment, while early 
non-responders will be given NB as an adjunct to BWL. The pilot will also examine whether 
augmenting behavioral treatment with NB results in weight loss and improvements in 
psychosocial functioning. These data will inform designs and provide effect size data to 
power larger definitive trials examining stepped care approaches with behavioral and 
pharmacological interventions for post-MBS.
 
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3 - Rationale/Significance
3.1 Problem Statement
MBS is the most effective treatment for severe obesity and associated sequalae. Despite 
MBS' overall efficacy, weight regain with recurrence and/or onset of medical and 
psychological comorbidities is common and a matter of great concern. Very little is known 
about post-MBS treatments for weight regain. 
3.2 Purpose of Study/Potential Impact
The goals of this proposal are to evaluate the feasibility and acceptability of evidence-based 
obesity treatments in post-MBS patients. All eligible subjects who experience weight regain 
after MBS will be given BWL. After one month of BWL treatment, "treatment response" will 
be determined based on early weight loss status because of its strong prognostic 
significance for optimal weight loss outcomes. Early weight-loss responders will continue 
BWL treatment, while non-responders will be given a pharmacologic agent to augment BWL 
treatment. This study aims to explore whether the addition of specific pharmacotherapy to 
BWL amongst initial non-responders improves outcomes. The study will compare the two 
treatment conditions and will examine within-group weight and psychosocial changes over 
time in the combined treatment condition; these data will serve as pilot data and represent 
effect-size estimates to design and power larger definitive treatment trials testing combined 
behavioral and pharmacological interventions and stepped-care approaches to prevent 
weight regain after MBS.
3.3.1 Potential Risks
The primary risks of this study are the BWL therapy, the pharmacologic therapy with NB, the 
assessment procedures, and lack of efficacy.                    
BWL: BWL is an established and widely-used intervention for obesity. The only foreseeable 
risks include some mild discomfort or embarrassment when discussing eating patterns or 
body image concerns. 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.  
Thus, the risks of BWL are judged to be minimal.
NB: NB combination is FDA-approved for the treatment of obesity. Both medications will be 
used in the present study. NB has demonstrated safety, tolerability, and efficacy for patients 
with obesity treated over much longer periods of time (>12 months) than in the present study 
(Greenway et al., 2010). 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. Less 
common side effects include risk of seizure, increase in blood pressure and heart rate, 
hepatotoxicity, and angle-closure glaucoma. 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 none of the observed events 
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were judged to be related to the study. In keeping with the FDA advisory pertaining to 
antidepressants, including bupropion, the following information will be included in the study 
consent forms: 
 "The U.S. Food and Drug Administration (FDA) has issued an Advisory cautioning health 
care providers, patients, and families to closely watch individuals taking bupropion for signs 
of their depression getting worse and for thoughts of killing or harming themselves, 
especially during the first several weeks that bupropion 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)."  
To monitor changes in depressive symptoms, patients will be asked to complete the
PHQ-9 at monthly clinic visits. The research clinicians, who are trained and supervised by 
licensed psychologists in suicidal assessment, will review PHQ-9s during the clinic visit, and 
will asked pointed questions pertaining to suicidality/suicidal ideation (i.e., suicidal thoughts, 
plan, means, and intent) using the Columbia Suicide Severity Rating Scale. If it appears, 
based on the clinical judgment of the research clinician, that the participant is experiencing 
significant adverse effects of the medication, the investigators and study physician will be 
consulted and a determination of whether to discontinue the medication will be made. If 
warranted, the participant will be given a referral and safety planning will be implemented. If 
any participant experiences adverse reactions, or if side effects are too severe, the 
medication will be discontinued.
Assessments: Completion of the assessment procedures may cause some mild anxiety or 
embarrassment to some patients.  Drawing blood from a vein to perform necessary 
laboratory tests is quite safe.  Sometimes a bruise will occur at the puncture site and on very 
rare occasions a blood clot or infection may occur.  If this occurs, appropriate treatment will 
be instituted immediately.
Failure to Improve: There is a chance that the patients will not lose weight or will gain 
weight during the study.  Patients will be withdrawn from the study if their clinical condition 
deteriorates to a significant degree.  Our experience with numerous RCTs is that this is quite 
rare. 
 
3.3.2 Potential Benefits
Subjects will receive potentially beneficial weight loss treatment(s) that are empirically-
supported. There is substantial importance in the knowledge to be gained in this study.  
Finding ways to identify, understand, and improve treatments for weight regain after MBS is 
critically important to address this important health problem.  The dearth of treatment 
research with this subgroup, particularly with pharmacological methods, is strikingly at odds 
with the public health significance and prevalence of obesity and MBS. Given the modest 
risks associated with the treatments and study procedures and the substantial potential 
knowledge to be gained, the benefit to risk ratio is very favorable.  
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4 - Study Objectives
4.1 Hypothesis
We hypothesize that the treatments will be feasible and acceptable to subjects, and that 
subjects will experience significant weight loss and improvements in psychosocial 
functioning. More specifically, it is hypothesized that early responders to BWL will show 
weight loss during the trial, while the addition of NB will aid early non-responders in 
achieving weight loss.
4.2 Primary Objective
This study aims to evaluate the feasibility and acceptability of adding a specific 
pharmacological treatment to behavioral treatment for non-responders among adults 
experiencing weight regain following MBS. A behavioral treatment will be given to all 
subjects as the primary treatment. After one month of behavioral treatment, patients who do 
not show a "response" (based on weight-loss data) will begin a trial of a specific medication 
(in addition to continuing the behavioral therapy); repeated multi-modal assessments will 
assess whether the combined approach augments the behavioral therapy.
We hypothesize that the treatments will be feasible and acceptable to subjects, and that 
subjects will experience significant weight loss and improvements in psychosocial 
functioning. More specifically, it is hypothesized that early responders to BWL will show 
weight loss during the trial, while the addition of NB will aid early non-responders in 
achieving weight loss.
4.3 Secondary Objectives (if applicable)
This pilot will also examine whether augmenting behavioral treatment with NB results in 
improvements in psychosocial functioning.
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5 - Study Design
5.1 General Design Description
A behavioral treatment will be given to all subjects as the primary treatment. After one month 
of behavioral treatment, patients who do not show a "response" (based on weight-loss data) 
will begin a trial of a specific medication (in addition to continuing the BWL); repeated multi-
modal assessments will assess whether the combined approach augments the behavioral 
therapy.
5.1.1 Study Date Range and Duration
Subjects will participate in the treatment trial for three months starting with an initial 
evaluation. If eligible, subjects will receive three months of BWL treatment (early non-
responders will be given an adjunct medication). When treatment ends, subjects will 
participate in a post-treatment evaluation.  Duration of the entire study will be three months. 
Anticipated start date is February 1, 2021 with an end date of January 31, 2023.
5.1.2 Number of Study Sites
1
5.2 Outcome Variables
5.2.1 Primary Outcome Variables
Primary outcomes will include: 1) feasibility, 2) acceptability, and 3) weight loss.
1) Feasibility will be determined by examining enrollment, number of sessions attended, 
compliance, and retention.
2) Treatment credibility and satisfaction will be examined via self-report.
3) To examine weight changes, we will examine percent total weight loss for the entire 
participant group. We will also compare percent weight loss for the two responder groups. 
5.2.2 Secondary and Exploratory Outcome Variables (if applicable)
Secondary outcomes will include psychosocial functioning such as eating-disorder 
psychopathology measured by the Eating Disorder Examination, depressive symptoms 
measured by the Patient-Health Questionnaire 9, and food craving measured by the Food 
Craving Inventory.
5.3 Study Population
Adults (aged 18-65) who experience weight regain after MBS (RYGB or LSG) will be 
recruited to participate in the study. Weight regain will be defined by the recommended 
definition of weight regain in the field, that is, weight regain defined as the percentage of 
maximum weight lost ([100*(post-nadir weight — nadir weight)]/(pre-surgery weight — nadir 
weight). Weight regain based on this definition was the best indicator of poor clinical 
outcomes.
5.3.1 Number of Participants
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N=25 adults who underwent MBS at the Yale bariatric surgery center will be recruited to 
participate in the study.
5.3.2 Eligibility Criteria/Vulnerable Populations
Inclusion criteria: To be included in the trial, a prospective participant must:
1.
Be in the age range ≥18 years of age and ≤65 years of age.
2.
Have a BMI ≥30 (or BMI ≥27 with a medical comorbidity) and BMI ≤ 50
3.
Have had laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy at a Yale 
bariatric surgery center
4.
Experience weight regain after surgery
5.
Had a physical during the past year
6.
Be an otherwise healthy subject without uncontrolled medical problems, as 
determined by the study physician and medical co-investigators (physical 
examination, laboratory studies).
7.
Read, comprehend, and write English at a sufficient level to complete study-related 
materials.
8.
Provide a signed and dated written informed consent prior to study participation.
9.
Be available for participation in the study for up to 3 months.
 Exclusion criteria: To enhance generalizability, exclusion criteria will be minimal, but 
consistent with study medication prescribing guidelines. A prospective participant will be 
excluded if he or she:
1.
Has a predisposition to seizures (e.g., subject with a history or evidence of seizure 
disorder, febrile seizures during childhood, brain tumor, cerebrovascular disease, or 
significant head trauma; has a family history of idiopathic seizure disorder or is 
currently being treated with medications or treatment regimens that lower seizure 
threshold).
2.
Has a history of anorexia nervosa or history of bulimia nervosa or current regular 
self-induced vomiting.
3.
Is currently taking a medication that is a contraindication to NB medication (e.g., 
MAOI, opiates).
4.
Is currently using other medications for weight loss.
5.
Has a history of allergy or sensitivity to bupropion or naltrexone.
6.
Has a co-existing psychiatric condition that requires hospitalization or more intensive 
treatment (such as bipolar mood disorders, psychotic illnesses, or severe 
depression)
7.
Has untreated hypertension with a seated systolic blood pressure > 160 mmHg, 
diastolic blood pressure > 100 mmHg, or heart rate > 100 beats/minute.
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8.
Has a history of congenital heart disease, cardiovascular disease, cardiac 
arrhythmias requiring medication, or a history of cerebrovascular pathology including 
stroke.
9.
Has current uncontrolled hypertension.
10. Has current uncontrolled Type I or Type II diabetes mellitus.
11. Has untreated hypothyroidism with a TSH > 1.5 times the upper limit of normal for 
the test laboratory with repeat value that also exceeds this limit.
12. Has gallbladder disease.
13. Has a history of severe renal, hepatic, neurological, chronic pulmonary disease, or 
any other unstable medical disorder.
14. Has a recent history of drug or alcohol dependence.
15. Is currently in active treatment for eating or weight loss.
16. Is currently participating in another clinical study in which the subject is or will be 
exposed to an investigational or a non-investigational drug or device.
17. Is breast-feeding or is pregnant or is not using a reliable form of birth control.
18. Reports active suicidal or homicidal ideation.
19. History of poor eye health.
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6 - Methods
6.1 Treatment - Drug
6.1.1 Identity of Investigational Product/New Drug
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. NB medication will combine naltrexone (50 mg/day) combined with 
bupropion (300 mg/day) taken daily.
Mechanisms of Action. Naltrexone, an opioid receptor antagonist, is approved to treat 
alcohol and opioid dependence [Marsh et al., 1999]. Naltrexone produces weight loss in lab 
animals but only minimal weight losses in people [Lavori & Dawson, 2007; Almirall et al., 
2014]. Bupropion operates through dopaminergic, noradrenergic, and nicotinic acetyl-
cholinergic mechanisms. Bupropion may target reward processes that drive eating 
behaviors, consistent with its FDA indication for treating nicotine dependence and reduced 
weight gain during smoking cessation [Kalarchian et al., 2013; Krimpuri et al., 2018]. 
Bupropion promotes weight loss [56]: in a meta-analysis of five trials of bupropion, the mean 
difference in weight loss was 2.77 kg (CI, 1.1 to 4.5) between bupropion and placebo groups 
at 6 months. White and Grilo [Almirall et al., 2012] reported preliminary, modest support for 
weight loss specifically in patients with obesity and binge-eating disorder.
NB Combination. The putative mechanisms of action for NB is especially relevant for 
reducing weight per hypothesized effects on brain regions implicated in the regulation of 
food intake based on research on the mechanisms of action of leptin [Almirall et al., 2014]. 
The anorectic effects of leptin result from its excitatory effects on pro-opiomelanocorin 
(POMC) neurons in the hypothalamus melancortin system [Chen et al., 2017; McElroy et al., 
2015]. Stimulated POMC signaling decreases food intake, increases energy expenditure, but 
is then inhibited by endogenous feedback [Chen et al., 2017]. Thus, combining these two 
drugs will stimulate POMC neurons (bupropion) plus block endogenous feedback that 
inhibits POMC activity (naltrexone) [Rusch & Andris, 2007; Almirall et al., 2014]. This 
synergistic model received support both in vitro and in vivo studies [Rusch & Andris, 2007, 
McElroy et al., 2016].
Obesity Outcomes. Recently, several large RCTs have reported that the combination of 
these two medications (Naltrexone/Bupropion) were effective in promoting weight loss in 
individuals with obesity [Rusch & Andris, 2007; Elder et al., 2018; Mond et al., 2010; 
Citrome, 2015]. 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 pills. Most recently, Apovian, Aronne, 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 
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following percentage of patients achieving at least 5% weight loss: 56% vs. 18% [Elder et 
al., 2008]; 52% vs. 15% [Gasior et al., 2017]. 
Risks. Several large-scale studies have found that this medication is safe and effective for 
the treatment of obesity [Rusch & Andris, 2007; Elder et al., 2008; Mond et al., 2010; 
Citrome, 2015]. 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 medication if 
symptoms develop. Risk of seizure may be minimized by adhering to the recommended 
dosing schedule and avoiding co-administration with high-fat meal. Increase in Blood 
Pressure and Heart Rate: Monitor blood pressure and heart rate in all patients, especially 
those with cardiac or cerebrovascular disease. Hepatotoxicity: Cases of hepatitis and 
clinically significant liver dysfunction observed with naltrexone exposure. Angle-closure 
glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically 
narrow angles treated with antidepressants. Use of Antidiabetic Medications: Weight loss 
may cause hypoglycemia. Monitor blood glucose. 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 as well as the verbal consent process: Naltrexone can 
cause withdrawal symptoms in individuals who are taking opioid pain medications or drugs. 
You should not participate if you are taking opioid medications of any kind and we will not 
include you in the study if we know or suspect you are using opiate-containing drugs. In 
addition to structured clinical diagnostic interviews with our clinical-research staff and 
medical record reviews, we will perform lab urine test at Quest with potential subjects 
suspected of opiate usage.
6.1.2 Dosage, Admin, Schedule (if applicable)
NB Pharmacotherapy Treatment Protocol. Participants who do not respond to the first 
month of BWL treatment will have NB added to their treatment for the remaining two months 
of treatment. NB medication will comprise naltrexone (50 mg/day) combined with bupropion 
(300 mg/day) taken daily. In a previously conducted pilot study, the NB final dosage 
consisted of 50 mg/day naltrexone combined with 300 mg/day bupropion XL, which closely 
approximates the newly approved NB combination (Contrave) dosage for weight loss 
[Greenway et al., 2009; Greenway, Fujioka & Plodkowski, 2010; Smith et al., 2013; Wadden 
et al., 2011], but with advantages. One advantage is that the formulations of both 
medications used in this study are already available at substantially lower cost than 
Contrave (75% savings for retail purchase) and the smaller size of pills (in blinding) is better 
for patients following MBS. Importantly, the immediate release (IR) version of Bupropion will 
be used in the present study as recommended by clinical guidelines for MBS populations. 
Because MBS can lead to changes in medication absorption due to alterations of gut 
anatomy, clinical practice guidelines recommend avoiding extended-release formulations of 
medications and using immediate release formulations (de Sousa Prado Geraldo et al., 
2014; Lorico, 2020, Vouri et al., 2021).  Additionally, using normal-release naltrexone rather 
than the sustained release formulation available only in Contrave is not seen as a 
pharmacokinetic disadvantage in any way. Despite a short initial serum half-life, the 
pharmacologic activity of naltrexone is long-lived, with an effective half-life of over 3 days, 
consistent with the terminal phase of plasma clearance [Lee et al., 1988]. For this reason, 
naltrexone has been used effectively in clinical treatment using daily or less frequent dosing. 
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In the proposed RCT, our dosage follows standard and long-standing dosage for both 
naltrexone and bupropion used for related psychiatric problems. Per previous RCTs, a 
dosing escalation approach will be used [Greenway, Fujioka & Plodkowski, 2010; Wadden et 
al., 2011]. This dosing will continue for the remainder of the RCT unless a patient develops 
intolerable side effects. If such occur, the physician may reduce the dosing to achieve 
tolerability. If the patient cannot tolerate the medication, has adverse effects, or is non-
compliant with medication for >7 consecutive days, they will be discontinued from the 
medication. Physician visits will be brief (10 -15 minutes), focusing on compliance with 
dosing and evaluating side effects. For participants taking medication for greater than 4 
weeks, a 7-day taper will be provided. 
Month 2
NB Medication
Study Day
Naltrexone Capsule
Bupropion IR Capsule
1-7
--
150 mg once a day
8-study end
50 mg
150 mg twice a day
6.1.3 Method of Assignment/Randomization (if applicable)
NA
6.1.4 Blinding and Procedures for Unblinding (if applicable)
Participants will not be blind to behavioral and medication treatments. There is no placebo 
for this trial because NB is an evidence-based weight loss treatment.
6.1.5 Packaging/Labelling
Refer to medication package insert.
6.1.6 Storage Conditions
The medication will be stored and dispensed at the Yale Investigational Drug Services 
pharmacy.
6.2 Assessments
Assessment Procedures. Table 1 summarizes the assessment schedule and measures. 
Assessments will be done by independent evaluators not involved in the treatment delivery 
and blind to early weight loss responder status.
 
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Assessment of Treatment Outcome and Time Course. 
Percent total weight loss (%TWL) (measured weight across time points). Per standard 
reporting guidelines, %TWL will be determined by the following formula: [(Initial Pre-
Treatment Weight) — (Post-Treatment Weight)] / [(Initial Pre-Treatment Weight)]*100.
 
Psychosocial/Behavioral Functioning listed below.
Informed consent will be obtained after complete study description, followed by interviews 
and surveys.
Interviews:
Eating Disorder Examination Interview — Bariatric Surgery Version (EDE-BSV) (18) an 
investigator-based interview will be the primary method for assessing loss-of-control eating, 
as well as severity of eating-disorder psychopathology.
Mini International Neuropsychiatric Interview-Version 7.0 (MINI) (19) is a brief structured 
interview for psychiatric disorders, which will provide data to characterize subjects.
 Anthropometrics: Weight and height will be measured to calculate body mass index.
 Self-Report Measures (baseline and repeated per Table 1):
Demographics: ethnicity/race, age, sex, education, and socio-economic status.                                
Eating Disorder Examination-Questionnaire Version with Instructions (EDE-Q-I) (20), 
which generates the same eating behavior and pathology data as the interview version, will 
be used across all assessment points given its low burden (in addition to the EDE-BSV given 
during major assessment points).
Food Craving Inventory (FCI) (21) assesses general and specific food cravings (relevant 
for NB) and comprises four subscales for different food groups. The FCI has been validated 
and psychometrically supported in studies with obesity and BED. The use of this craving 
instrument will allow direct comparison to the leading NB non-surgical obesity trials (14).
Patient Health Questionnaire-9 (PHQ-9) is a brief and widely-used measure of depression 
in diverse medical settings (22). Post-MBS depression was associated with poorer MBS 
outcomes in some studies and is relevant to the study medication.                                                                
Treatment Variables: Credibility ratings will be examined before beginning treatments and 
again after completing treatments. Treatment Compliance for BWL will include session 
attendance and self-monitoring compliance and counts, and pill count method for 
medication.
Adverse Events will be collected during clinic visits using adverse event checklist of the 
most commonly reported adverse events for NB to monitor safety.
6.2.1 Efficacy. NB is an FDA-approved medication for weight loss among individuals with 
obesity.
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6.2.2 Safety/Pregnancy-related policy
Given the uncertain effects of medication during pregnancy, the following precautions will be 
taken for women of reproductive age who are sexually active and non-responders (those 
who will be starting NB medication) : 1) a pregnancy test will be required; 2) will be required 
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, and 3) if a woman becomes pregnant after study entry, 
her medication will be discontinued. 
6.2.2.1 Adverse Events Definition and Reporting
Adverse event data will be collected on an on-going basis. Adverse events data will be 
reviewed by the PI and co-investigators throughout this trial. A summary of adverse events 
will be provided to the Yale IRB yearly during the annual renewal review process. Any 
serious or unanticipated adverse events will be reported to the Yale IRB within 48 hours.  
6.2.3 Pharmacokinetics (if applicable)
6.2.4 Biomarkers (if applicable)
6.3 Study Procedures
Subjects will participate in an initial evaluation to determine eligibility. Eligible participants 
who provide written informed consent will start BWL treatment which last for three months. 
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 obesity, binge-eating disorder, and histories of bariatric surgery. 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 closely that used by Wadden et al. 
(2011) in the COR-BMOD Trial testing BWL and NB/placebo medication for obesity, but 
modified for post-MBS patients. 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. After one month of BWL treatment, "treatment response" will be 
determined based on early weight loss status because of its strong prognostic significance 
for optimal weight loss outcomes. Early weight-loss responders will continue BWL treatment, 
while non-responders will be given a pharmacologic agent (NB) to augment BWL treatment 
for the remaining two months of treatment. Outcomes assessments will be done by 
independent evaluators not involved in the treatment delivery and blind to responder status. 
Participants will be asked to complete self-report surveys at the baseline evaluation, monthly 
during treatment, and at the end of treatment.  For participants starting NB medication, they 
will be asked to have labs drawn to examine liver values for safety before starting medication 
and again after being on the medication for one month.
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6.3.1 Study Schedule
Assessment Points
Baseline during rx 
1-Month
during rx 
2-Month 
 POST rx 
3-Month
Medical History, Height, MINI Psychiatric 
Interview,Demographics (i.e., sex, race)
·
EDE-BSV Interview, Treatment 
Credibility/Satisfaction
·
·
EDE-Q-I, FCI, PHQ-9, GPAQ, Weight, 
Adverse Events, Compliance
·
·
·
·
6.3.2 Informed Consent
Research clinicians (who have completed IRB and ethics training) will meet with potential 
participants to discuss the study and all procedures, treatments, and risks and obtain written 
informed consent. All potential participants will be free to decide whether or not to participate 
and are free to withdraw from the study at any time. Alternative treatments (both 
psychosocial and pharmacological options) will be discussed and referrals offered if 
requested. The written informed consent will be obtained after opportunity to discuss and 
address all questions. 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. A decision to not participate 
or to discontinue participation would not adversely influence future interactions with Yale, 
Yale School of Medicine, or the investigative group. The process of informed consent may 
be completed in-person or remotely. If completed remotely, the consent process will be 
conducted by one of two methods: 1) a consent form will be mailed or emailed to the 
participant. The participant will then mail back (or email back) the signed consent form to the 
study team for signature or 2) the consent form will be completed using the validated Part 11 
version of REDCap. A copy of the final consent (signed by both parties) will be mailed or 
emailed to the participant for his/her records. For all consenting, a meeting will be held in-
person or remotely (e.g., via Zoom) to discuss the study and informed consent process.
6.3.3 Screening
Pre-Screening: Participants responding to recruitment efforts 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 or 
remotely by trained supervised research clinicians (doctoral level and/or advanced trainees).
 
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6.3.4 Recruitment, Enrollment and Retention
Participants will be recruited from the Yale Bariatric/Gastrointestinal Surgery Center of 
Excellence via flyers and posters at the bariatric center, provider referral, and patient 
mailings. Specifically, the bariatric team agreed to identify potential subjects during routine 
medical post-surgical evaluations and support group meetings. In addition, flyers and 
posters alerting potential subjects to the treatment study will be placed in the Yale 
Gastrointestinal Surgery/Bariatric Center. Flyers will also be placed on our program’s 
website. Letters will be mailed to individuals who had MBS within the past five years at Yale. 
For the mailing, we will utilize the Yale Joint Data Analytics Team (JDAT) to identify potential 
subjects. JDAT creates updated list of individuals who have recently had bariatric surgery at 
Yale and ensures that letters are not sent to subjects who have opted out of research at 
Yale. Yale JDAT is able to identify potential subjects by specific parameters related to 
inclusion criteria such as age (18-65), and MBS (laparoscopic Roux-en-Y gastric bypass or 
sleeve gastrectomy) performed at Yale. A study flyer and letter describing the study 
(approved by the Yale IRB) will be mailed. If interested, individuals will have the opportunity 
to contact the study team for screening. Previous experience with this recruitment process 
has been very successful and without adverse reactions (i.e., for NIH/NIDDK-funded 
bariatric trial R01 DK098492). Participants who opted out of research will not be 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 in-person or remote (e.g., via Zoom) 
assessment. 
After initial contact, research clinicians (who have completed IRB training) will meet with 
potential participants to discuss the study, the treatments, the assessments, the follow-up 
period, and the informed consent procedures and forms. Clinicians will answer any 
questions and obtain written informed consent. A copy of the signed informed consent form 
will be given to the participants and the original will be kept in the participant's file. All 
potential subjects and/or participating participants are free to decide whether or not to 
participate and are free to withdraw from the study at any time. Alternative treatments would 
be discussed 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.
6.3.5 On Study Visits.
Participants may attend visits in-person at the Yale Program for Obesity, Weight, and Eating 
Research or remotely.
6.3.6 End of Study and Follow-up
Participants will be asked to attend a post-treatment (end of study) assessment, which will 
consist of an interview, measured weight, and completion of self-report surveys as indicated 
in the assessment schedule grid.
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6.3.7 Removal of subjects
Withdrawal/attrition from treatments will be examined. Use of other treatments during the 
study will be assessed and considered in analyses. Patients will be asked about all forms of 
treatments during major assessments. Criteria for removal of patients from the study may 
include worsening depression, suicidal ideation, or failure to comply with medication.  
Previous experience suggests that worsening clinical status is rare; in such cases, Dr. Ivezaj 
and study physician would determine whether to remove the person from the study and 
provide referrals.
6.4 Statistical Method
6.4.1 Statistical Design and Analyses
To examine weight changes, we will examine percent total weight loss for the entire 
participant group. We will also compare percent weight loss for the two responder groups. 
We will use linear mixed effects models with treatment (BWL or BWL+NB medication), time 
and the interaction between treatment and time to examine percent weight loss. We will 
construct a 95% confidence interval for percent weight loss within the non-responder arm 
based on the mixed model above.   
7 - Trial Administration
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
A compound consent form will be used (see attached).
7.2 Institutional Review Board (IRB) Review
IRB approval will be required prior to study enrollment.
7.3 Subject Confidentiality
Protecting Confidentiality: To ensure confidentiality, all participant research records will be 
kept in locked files in the Department of Psychiatry at the Yale University School of Medicine 
or on secure server at Yale.  All research forms, interviews, measures, audiotapes, and 
computer data will be coded to ensure anonymity and will be kept in separate locked files.  
Data analysis and reporting will not allow for identification of any individual participants. All 
research personnel will be trained and supervised around confidentiality issues. The training 
will include formal Yale IRB modules with testing certification as well as HIPAA guidelines to 
follow around confidentiality. 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. Research records may be the subject of an audit by a regulatory 
agency. Organizations which have a responsibility for protecting human subjects, including 
the Yale Human Investigation Committee (HIC), may have access to the research records. 
Additionally, the funding agency (APF) may have access to the research records. The 
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subject'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 HIC and HIPAA procedures.
 
7.4 Deviations/Unanticipated Problems
Deviations/unanticipated problems will be reported to the IRB.
7.5 Data Collection
Data collection is done by study staff who received and completed Yale trainings in human 
subjects, HIPAA, and good clinical practice and are approved by the HIC.
7.6 Data Quality Assurance
Data is cleaned and monitored by the study team. 
7.7 Study Records
All participants will be assigned a study ID. Subsequently, participants will be identified only 
by that ID. 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 ID and date. Data will be saved on a secure server. 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.
7.8 Access to Source
7.9 Data or Specimen Storage/Security
Data are stored on a secure server and in locked file cabinets on a secure floor and building.
7.10 Retention of Records
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.
7.11 Study Monitoring
Monitoring for data integrity and safety will be the responsibility of the investigators and the 
Yale IRB (Human Investigation Committee). The data safety monitoring plan (DSMP) for this 
clinical trial focuses on close monitoring by the principal investigator and co-investigators.
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7.12 Data Safety Monitoring Plan
The investigators will perform study oversight and monitoring including data quality, storage, 
confidentiality, and issues covered in good clinical practice. In addition, the principal 
investigator will promptly report excessive adverse events and any serious adverse events to 
the APF and to the IRB at the Yale University School of Medicine. Other (less serious) 
adverse events will be reported to the IRB periodically during regular reporting periods. 
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews quarterly. During the review process the 
principal investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment.
The principal investigator and co-investigators will review the following: 
1.
Recruitment and retention for the study and compare them to target rates.
2.
Rates of data completeness and availability of primary outcome data
3.
Occurrence of AEs and SAEs
4.
Report of study progress since the last report.
5.
Rates of recruitment of women and minorities with respect to targets.
These reports are generated by the study coordinator each quarter (reviewed by PI and co-
investigators). If adverse events occur in greater magnitude or frequency than expected 
these will be reported to the APF and HIC prior to scheduled reports. The Principal 
Investigator will assume full responsibility for reporting serious and non-serious and 
unanticipated adverse events. 
Because the projected effect sizes may not be large enough for detection during interim 
analyses, we are not proposing a preliminary analysis of accumulating efficacy and safety 
data by treatment assignment. Instead, we will review twice-yearly aggregate data that 
contains screening data, baseline demographics, retention data, serious adverse events 
data, as well as accrual status, and any other data that will help in the assessment of the 
clinical trial. 
            Risk Assessment: 
The risks associated with the current study are deemed greater than minimal. Although we 
do not view the risks associated with the study medication as minimal risk, the established 
safety and validity of the Naltrexone/Bupropion (FDA-approval of Contrave for obesity) RCTs 
suggest that the study procedures and medications are not high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual. 
Therefore, we provide a plan for monitoring the data and safety of the proposed study as 
follows:
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Measurement and reporting of adverse events.
Adverse event data will be collected on an on-going basis. Adverse events data will be 
reviewed by the PI and co-investigators throughout this trial (see Table below). A summary 
of adverse events will be provided to the Yale IRB yearly during the annual renewal review 
process. Any serious or unanticipated adverse events will be reported to the NIH and to the 
Yale IRB within 48 hours.  
       The frequency of data review is summarized in the following table:
 Table
Data type
Frequency of Review by PIs and 
Research Team
Table 
1
Subject accrual
Monthly
Table 
2
Treatment completion rates 
(retention/attrition)
Quarterly
Table 
3
Adverse and serious adverse event 
rates
Quarterly
Table 
4
Checklist for DSMB
NA
 
          Attribution of Adverse Events:  
Adverse events will be monitored for each subject participating in the study and attributed to 
the study procedures by the investigators according to the following categories:
1.
Definite: Adverse event is clearly related to the investigational procedure/agent.
2.
Probable: Adverse event is likely related to the investigational procedure/agent.
3.
Possible: Adverse event may be related to the investigational procedure/agent.
4.
Unlikely: Adverse event is likely not to be related to the investigational 
procedure/agent.
5.
Unrelated: Adverse event is clearly not related to the procedure/investigational agent.
              Plan for Grading Adverse Events:  
The following scale will be used in grading the severity of adverse events noted during the 
study:
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1.
Mild adverse event
2.
Moderate adverse event
3.
Severe adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.
4.
Severe adverse event that may jeopardize the participant's health and requires 
medical or surgical intervention to prevent death, disability/incapacity, or congenital 
anomaly.
5.
Fatal adverse event
 
Plan for events to the Yale IRB that are unexpected AND related AND involve risk of harm to 
subjects or others:
          The PI will report any incident, experience, or outcome that meets all three of these 
conditions to the IRB immediately: a) unexpected (in nature, specificity, severity, or 
frequency); b) related (probably or definitely); and c) places participants or others at greater 
risk of harm (physical, psychological, economic, legal, or social) than previously known or 
recognized. Following immediate reporting, an event will be reported using Form 710 FR 4 
(Unanticipated Problem Involving Risks to Subjects or Others Reporting Form) to the IRB 
within 5 calendar days of it becoming known to the PI.
 
Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol's research monitors, e.g., study sponsors, funding and regulatory agencies, and 
regulatory and decision-making bodies: 
              For the current study, the following individuals, funding, and/or regulatory agencies 
will be notified:
1.
All Co-Investigators listed on the protocol
2.
American Psychological Foundation
 
The investigators will conduct a review of all adverse events upon completion of every study 
subject. The investigators will evaluate the frequency and severity of the adverse events and 
determine if modifications to the protocol or consent form are required.
 
              Procedures for providing follow up care:
Medical monitoring will occur at all clinic and follow up visits and medical care will be 
provided if warranted. If a study participant experiences any psychiatric symptoms or 
distress (e.g., depressive symptoms or suicidality) at any stage of study participation he/she 
will receive short-term treatment and support from the study treatment team (including 
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psychologists) and will be connected to a local emergency department (e.g., the Crisis 
Intervention Unit at Yale-New Haven Hospital) and his/her physician or therapist for ongoing 
care.
Measurement and reporting of subject accrual, adherence to inclusion/exclusion criteria.
Review of the rate of subject accrual and adherence to inclusion/exclusion criteria will occur 
regularly by the PI and co-Investigators. These reviews will help to assure that participants 
meet eligibility criteria and ethnic diversity goals.
Measurement and reporting of participant treatment completion rates.
Participation rates (retention and attrition) will be reviewed on an ongoing basis by the PIs 
and co-investigators to identify any potential problems, and formally twice-yearly.  Any 
differential dropout and/or higher than expected dropout will be reviewed by the investigators 
to determine whether any problems are present and what, if any, corrective action needs to 
be taken.
During the reviews, if the investigators have concerns about whether attrition has reached a 
level that might inhibit the ability of the study to address its primary aims, they will suggest a 
meeting to discuss methods for improving subject retention. Previous pharmacotherapy 
studies for binge-eating disorder and obesity (with comparable time frames for 
pharmacotherapy) have reported attrition rates between 20% and 38%.  Studies of NB for 
obesity treatment reported attrition of 30% to 45%. Thus, "trigger points" for review and 
discussion by principal investigator and research staff will be:  35% ("low alert"), 40% ("mid 
alert"), 45% ("high alert"), 50% ("extreme alert").  With early alerts to problems, action would 
be taken to avoid higher level alerts; if a higher level alert should arise, more drastic actions 
would be taken. 
Trial Stopping Rules
Given that this study is deemed greater than minimal risk to human subjects, it is more likely 
that attrition or difficulty in recruiting adequate numbers of participants will require stopping 
the trial than would excess adverse events. However, as outlined, adverse events will be 
monitored in all participants, and the PI will alert the Yale IRB and the APF if a larger (or 
more serious) than reasonably expected adverse event rate should occur. Other potential 
issues relating to stopping rules for this trial include:
1.
 New Information 
It is unlikely that any new information will become available during this trial that would 
necessitate stopping the trial. If new safety data (i.e., pertaining to short-term use of the 
study medication) become available, this will be evaluated.
1.
 Limits of Assumptions
It is possible that excessive attrition and/or missing data could limit the value of data 
analysis. This will be evaluated yearly and if present, considered in relation to potential 
effects on the power to detect differences in the primary outcomes. 
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The following actions would be taken at each level of alert:
(1) Low-level alert = Review of potential problems by PI.
(2) Mid-level alert = Meeting with co-investigators to discuss approaches to minimize further 
losses to follow-up/dropouts.
(3) High-level alert = Meeting with co-investigators to determine further alterations of study 
protocol to complete the study with no further losses.
(4) Extreme-level alert = In the unlikely event of a 50% dropout rate prior to the mid-study 
time point, discontinuing the trial would be considered.
1.
 Limits of Rules
There are other situations that could occur that might warrant stopping the trial and/or 
including a section on the safety report entitled "Other situations that have occurred since 
the last safety report that warrant discussion" to allow for communication of concerns.
7.13 Study Modification
Study modifications will be submitted to the HIC for review and approval.
7.14 Study Discontinuation
The HIC will be notified if study discontinuation is warranted. 
7.15 Study Completion
Study completion is expected 1-2 years after first enrollment.
7.16 Conflict of Interest Policy
The study team declares no conflicts of interest.
7.17 Funding Source
American Psychological Foundation
7.18 Publication Plan
The PI (Dr. Ivezaj) ensured that the clinical trial is registered on ClinicalTrials.Gov before 
enrollment of the first participant. Initial registration data will include information about the 
study, including the grant title and number, the local IRB number and contact information, 
responsible party, description of study intervention and primary outcomes, study location and 
inclusion/exclusion criteria. Data submitted as study results will include participant flow, 
demographic characteristics, clinical characteristics at baseline, outcomes, statistical plan 
and findings, adverse events, the study protocol, and administrative information. The 
following statement will be included in the informed consent document for this study: "A 
description of this clinical trial will be available on http://www.ClinicalTrials.gov 
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(http://www.ClinicalTrials.gov), as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time." Yale University has an internal policy to ensure 
that clinical trials are registered and results are reported in compliance with policy 
requirements.                     
In addition, results will be reported at national/international conferences and published in 
peer-reviewed journals. Finally, data will be used as pilot data for larger, definitive NIH 
RCTs.
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Appendices
Appendix #
Title
Section
Topic
NA
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List of Tables
Table 1: Assessment Schedule
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