Assessment of and Treatment Applied to Food Addiction to Encourage Self-Management of Obesity in a Rural Healthy Behaviors Clinic
Phase: PHASE4
Conditions: Obesity
Sponsor: University of Nebraska

Assessment of and Treatment Applied to Food Addiction to Encourage Self-Management of Obesity in a 
Rural Healthy Behaviors Clinic   
 
NCT03431831 
 
31 Mar 2017 
 

Study Protocol and Statistical Analysis Plan 
 
Summary 
The purpose of this pilot study is to assess obese clients for two phenotypes, those testing positive and 
those testing negative for Food Addiction (FA) (Yale Food Addiction Scale, YFAS) and determining the 
efficacy of four treatments: usual care (IC, dietary and physical activity instruction), individual 
motivational interviewing alone (MI), individual MI with pharmacotherapy (MI+P) for improving outcome 
measures within each phenotype, and pharmacological therapy (P). 
 
Background/significance  
The ongoing epidemic of obesity is of great concern, especially among rural Americans, where the rate 
of obesity is greater than that of Americans living in urban areas. The costs related to obesity and its 
comorbidities continues to rise and includes the psychological implications of obesity. Scotts Bluff has an 
overweight/obesity rate of 71% according to the 2014 Scotts Bluff County Health Dept Community 
Health Assessment. Recently it has been suggested that addiction-like tendencies toward foods, 
(especially highly processed foods that are high in fat and sugars) (HPFS) is contributing to the epidemic 
(Schulte 2015, Flint 2014, Iozzo, 2012; Pursey, 2014). In order to assess addictive-like eating behavior, the 
Yale Food Addiction Scale (YFAS) has been developed in relation to DSM V Substance-Related and 
Addictive Disorders (SRAD) symptom criterion or clinical impairment/distress. The YFAS has been tested 
to be psychometrically sound. One study using the YFAS found that nearly 20% of obese persons tested 
positive for food addiction (FA), yet few if any interventions to address obesity have specifically targeted 
individuals who test positive for FA. 
Empirical evidence is growing for the idea that food addiction may be a contributor to obesity and 
eating-related problems (Gearhardt, Corbin, & Brownell, 2009a,b). This hypothesis proposes that highly 
processed foods, high in fat and sugar (HPFS) (e.g., pizza, chocolate, chips), may be capable of triggering 
an addictive response in individuals with vulnerable characteristics (e.g., impulsivity). Early evidence in 
animal and human studies suggests that HPFS foods may activate reward related neural circuitry in a 
similar manner as drugs of abuse. Additionally, behavioral indicators of substance-use disorders, such as 
loss of control and use despite negative consequences, have been observed in response to HPFS foods. 
Shared mechanisms (e.g., reward dysfunction, emotion regulation difficulties) and genetic profiles also 
appear to contribute to both food addiction and substance-use disorders. Thus, existing evidence 
demonstrates biological and behavioral parallels between individuals with food addiction and substance-
use disorders and suggests that HPFS foods may be most likely to have an addictive potential for some 
individuals. 
The Yale Food Addiction Scale (YFAS) is currently the only validated measure to assess symptoms of food 
addiction. The current version is the YFAS 2.0 is a 35-item self-report questionnaire that applies the 
DSM-5 diagnostic criteria for substance-use disorders to consumption of HPFS foods. The YFAS 2.0 
provides two scoring options: a symptom count (a sum of the eleven diagnostic criteria) and a diagnostic 
threshold that reflects the criteria for a substance dependence diagnosis (the presence of two or more 
symptoms plus clinically significant impairment or distress). 

The YFAS has good internal consistency ranging from á = .76.92 and demonstrates convergent validity 
with measures of eating pathology (e.g., emotional eating, food craving) and incremental validity in 
predicting binge eating frequency above and beyond existing measures. The YFAS has been used to 
assess food addiction in both community and treatment-seeking samples. Reducing highly processed 
foods, especially those high in fat and sugar Highly processed foods that are high in fat and sugar (HPFS) 
are typically low-nutrient simple carbohydrates (LNSC). There is growing recognition that the nature of 
carbohydrates consumed is an important dietary consideration. A key to healthy eating is reducing 
consumption of LNSC(e.g., sugars and starches) in favor of complex carbohydrates [e.g., fruits, vegetables 
(except potatoes), legumes, and whole grains] and minimally processed proteins (nuts, fresh lean 
meats).  
Low-nutrient simple carbohydrates: LNSC are composed of single chain carbon atoms and are rapidly 
digested and absorbed, resulting in rapid peaks in blood glucose and insulin, followed by a drop in blood 
glucose and increased perceptions of hunger. Commonly, these foods have little nutritional value and 
tend to be high in calories. They include processed and homemade foods made with white flour, sugar, 
and corn syrup such as white breads, tortillas, cold cereals, pastas, candies, pastries, and sugar-
sweetened beverages (e.g. fruit drinks, soda, and sports/energy drinks), many of which are commonly 
consumed in American households. Particularly concerning is that these foods may have addictive 
properties, affecting dopamine levels. LNSC contribute to many chronic diseases, including type 2 
diabetes, hypertension, cardiovascular disease, obesity, inflammation, and metabolic syndrome, and 
acute conditions such as hunger, satiety, mood, and glycemic load. 
High dietary intake of LNSC is associated with lower HDL cholesterol concentrations, an important 
coronary risk factor. Obesity itself is also associated with low HDL cholesterol levels, as well as increased 
triglyceride levels, in both children and adults. Results from interventions limiting LNSC intake show 
promise, with individual studies showing decreases in one or more variables of energy intake, blood 
pressure, lipid levels, and weight and improved glucose tolerance and hyperinsulinemia in adults age 18 
and older. 
Complex carbohydrates and natural fats: There is growing evidence that deriving dietary carbohydrates 
primarily from complex (e.g., whole fruits and vegetables, legumes, whole grains) rather than simple 
carbohydrate sources may help reduce the risk of developing or aid in the treatment of cardiovascular 
disease, type II diabetes, and metabolic syndrome and may aid in weight loss. These benefits are thought 
to derive from the non-starch polysaccharide, dietary fiber, and possibly other components of these 
foods. Therefore, limiting HPFS foods and increasing CC and natural fat intake is an integral component 
of our intervention and is consistent with recommendations advocating intake of slowly absorbed 
complex carbohydrates rather than rapidly absorbed simple carbohydrates. Healthy fats such as nuts, 
fresh lean meats, avocados, olive oil are also absorbed slowly and have nutrients important in reducing 
risk of developing cardiovascular disease, type II diabetes and metabolic syndrome. 
Motivational Interviewing to limit HPFS intake and increase CC and natural fat intake The framework for 
the proposed study was adapted from the Predicting and Changing Behavior Theory (PCBT), which 
proposes that an individuals’ attitudes/beliefs (perceptions toward a behavior), perceived norms 
(including social pressures within a culture or family), and perceived behavioral control (self-efficacy or 
belief about the ease or difficulty of performing a behavior) are the primary determinants influencing 
intention to engage in a particular behavior. The PCBT has been used to predict behaviors such as weight 

loss, physical activity, and self-efficacy for healthy eating in American populations. However, few, if any, 
studies have focused on using this approach to encourage obese Americans to reduce their HPFS intake 
and increase their CC and natural fat intake in an effort to move them toward self-management of 
obesity, nor have they assessed the impact of such interventions on their diet and/or biometrics. Our MI 
intervention with and without pharmacotherapy is designed to effect behavior change by sharing 
information on the benefits of limiting HPFS intake and increasing CC and natural fat intake (addressing 
attitudes/beliefs), and providing support to increase perceived behavioral control by decreasing 
participants ambivalence and barriers (addressing self-efficacy), which will support participants in 
limiting their HPFS intake and increasing their CC intake. MI is evidence-based, client-centered, and 
individualized, empowering individuals to establish their own realistic goals for behavior change by 
emphasizing personal choice and affirming client decisions. 
 
Pharmacotherapy for Obesity/Addiction (naltrexone-bupropion) 
Recent studies have assessed the efficacy of combination treatments of long-acting acting opioid 
antagonists (naltrexone) and antidepressant drugs (buproprion) in lowering the body weight of obese 
patients. Buproprion seems to have a complementary effect of decreasing hunger in combination with 
naltrexone, producing significant long-term decreases in weight. A multicenter phase III trial was 
conducted that randomly assigned 1,742 overweight individuals to receive an oral preparation of a 
sustained release pharmaceutical. The intervention continued for 56 weeks after which mean reduction 
in body weight was significantly higher in the pharmaceutical groups than placebo groups. 
Pharmaceutical groups were treated with naltrexone 16 mg plus buproprion and 32 mg naltrexone plus 
buproprion. In the proposed study, dosing protocols will be followed for treatment of obesity: 1 tablet 
(90mg/8mg) initially week 1; increase by 1 tablet/day each subsequent week until daily maintenance 
dose of 2 tablets twice daily (360 mg bupropion/32 mg naltrexone) is achieved at the start of week 4. 
Use will be discontinue used at month 4 if no clinical response is observed. 
Contribution to Science 
This study addresses a critical topic and will contribute to the science of treating obese patients, 
particularly those with FA as diagnosed by the YFAS. We hypothesize that using a team of 
interventionists delivering an addiction-adapted MI intervention to support obese patients in reducing 
their HPFS intake and increasing their CC and natural fat intake will enhance the success of our 
interventions, thereby helping reduce the incidence of addiction/overweight/obesity, improving 
biometric measures, and reducing the risk for comorbidities associated with obesity. Use of the YFAS and 
evaluating the interventions in both obesity phenotypes, is expected to help identify better targeted 
approaches for addressing self-management of obesity by clients in each phenotype. Though this study 
focuses on a rural population, investigators anticipate that this approach can be adapted to broader 
populations, including those in urban settings. 
 
 
 

Statistical justification for the total number of subjects needed to complete the research to achieve the 
scientific objectives. 
The prevalence of FA is estimated to be 25% in the population of urban adult women who have a BMI 
classification of overweight or obese. Using this prevalence along with a medium effect size, a statistical 
power analysis was performed for sample size estimation with G*Power 3.1. The design is a stratified 
four-group design with a pre and post measurement. Stratification by obesity phenotype (positive or 
negative for FA) will occur first, followed by random assignment to one of four treatment groups 
[Information Control (dietary and physical activity instruction), MI alone(diet and physical activity 
instruction supported by MI), MI((diet and physical activity instruction supported by MI+P(Contrave). 
Using an f = 0.25, an alpha = .05 and power = 0.95, the a priori F test, analysis of variance, omnibus, one-
way model gives a projected sample size of 252. As a pilot study, this study is underpowered for 
statistical hypothesis testing, and analyses will focus on descriptive statistics, estimation of effect sizes, 
and hypothesis generation and a sample of 40 eligible patients will be enrolled (10 in each group). This 
meets the pilot study guideline of at least 10% of a fully powered trial and remains realistic in terms of 
time and cost (Hertzog, 2008) while allowing for 50% attrition. It is expected that 25% of the population 
will meet the criteria of FA and therefore will need to screen and consent a total of 160 participants to 
reach the 40 people positive for FA. No more than 160 subjects will be consented for the entire pilot 
study. 
 
Proposed methods/approach  
Investigators propose assessing obese clients with the YFAS as part of their intake once they are referred 
to the Healthy Behaviors Clinic by Regional West physicians/practitioners. A nurse researcher with 
expertise in MI and a nurse practitioner will perform intake assessments, obtain consent and randomly 
assign participants in each phenotype (positive or negative for FA) to one of three treatment groups 
(usual care, individual MI alone, and individual MI with pharmacotherapy). Interventions will occur over 
6 months. A clinical psychologist with expertise in the YFAS (University of Michigan) will serve as a 
consultant on this project and a registered dietitian (University of Nebraska Lincoln) will serve as a co-
investigator. 
 Investigators expect that MI and MI+P and P will be more effective in improving outcome measures than 
IC. We also expect that response to the treatments will differ between the two obesity phenotypes 
(those testing positive and those testing negative for FA). 
To determine if MI alone or MI+P or P is effective in treating obese patients with and without FA (based 
on the YFAS) as determined by : 
 
-Higher MI confidence, importance and readiness to change scores 
-Reduced intake of foods that are highly processed and high in fat and sugar (HPFS) and 
increased intake of complex carbohydrate foods(fresh fruits, vegetables, whole grains) and 
minimally processed proteins (nuts, fresh meats) (ASA24-2016® dietary recall) 
-Improved biometric measures (BMI, body composition, waist circumference, and blood 
pressure) 

-To determine whether the two obesity phenotypes (with and without FA) differ in their 
response to the four treatments. 
 
Initial Screening for Eligibility (Suicidal Ideation, Pregnancy test (urine test), Lactation, Recruitment): 
Participants will be recruited from obese patients referred to the Healthy Behaviors Clinic by Regional 
West Physicians. Nurse researchers who work at the Healthy Behaviors Clinic will inform potential 
participants about the study and, if they agree to participate, will consent them. 
Both treatment groups,Those who test positive for and those who test negative for FA (food addiction) 
will be assigned to one of four treatment arms, IC, MI, MI/P and P. All will receive dietary and exercise 
information. After consenting, each participant be administered the YFAS to determine their obesity 
phenotype (positive or negative for FA). Participants within each phenotype will be randomly assigned to 
one of the intervention (MI or MI+P, or P) or the IC information control (diet and physical activity 
instruction, which will be no less than current standard of care) treatment groups using a randomization 
schedule (assignments in numbered, sealed, opaque envelopes; one set for each phenotype) 1:1:1:1 
ratio, provided by our statistician, Dr. Struwe. Phenotype assessment and treatment assignment will 
continue until the sample size (n=10) is met for each phenotype-treatment group category. Those in the 
control group will be seen at the same time periods as each treatment group to maintain their 
interaction time with the clinic. They will receive diet and exercise instruction at each time point.  
 
Intervention Conditions (MI, MI+P): MI is theorized to decrease a patients ambivalence and increase 
his/her perceived behavioral control (self-efficacy) for limiting HPFS and increasing CC intake by 
emphasizing personal choice and control in decision-making and by affirming the patients self -
management ability. Interventionist nurses will deliver MI sessions following data collection at baseline, 
1, 2,3, and 4 weeks and 2, 3, 4, 5, and 6 months to promote sustained behavioral change.50 A written MI 
algorithm will be used to ensure uniform implementation of the intervention. 
MI will be operationalized by the nurse asking the patient about his/her knowledge, limiting 
HPFS/increasing CC and natural fat intake, defining FA, and explaining why it is important to limit their 
HPFS/increase their CC and natural fat intake. The nurse will ask the patient to rate the importance of 
limiting HPFS/increasing CC and natural fat intake (scale of 1-10) and their confidence in their ability to 
do so (scale of 1-10). The nurse will focus on the lower score and ask the patient why they chose that 
score and what they thought it would take to increase the number. If the patient rates the importance of 
understanding of limiting HPFS/increasing CC and natural fat intake low, the nurse will provide 
information on the benefits of limiting HPFS/increasing CC and natural fat intake to reduce the their risk 
of obesity, diabetes, heart disease, and numerous other co-morbidities associated with overweight. If 
the patient rates their confidence in their ability to limit HPFS/increase CC and natural fat intake as low, 
the nurse will provide the patient with strategies to decrease barriers and increase confidence, such as a 
list of healthy snack food choices, stepped changes (3 sodas per day to 2 sodas and 1 water per day, 
etc.), and having the patient choose healthy foods at the store. The same questions will be asked at each 
time point. 

Nurse responses will be tailored to the specific motivational issues of each individual patient at each 
time point. During each session, the nurse will document the patients responses to the MI algorithm 
(levels of confidence, importance, and readiness to change), their perceived barriers and concerns, and 
suggestions to address them/setting achievable goals. The MI documentation form will ensure that all 
nurses collect the same data and provides a record that the nurses can reference during their sessions to 
help them adjust each MI session to the patients’ individual needs. If a patient reveals a new barrier that 
is not  included in the training materials, the nurses will meet with team members to discuss the new 
barrier and strategies to address it will be shared with all interventionists. 
In the group with pharmacotherapy added to the MI, the naltrexone-buproprion (Contrave) protocol will 
be added to the patients intervention. Dosing protocols will be followed for  treatment of obesity: Orally, 
1 tablet (90mg/8mg) initially week 1; increase by 1 tablet/dayeach subsequent week until daily 
maintenance dose of 2 tablets twice daily (360 mg bupropion/32 mg naltrexone) is achieved at the start 
of week 4. Use will be discontinued at month 4 if no clinical response is observed. This drug (Contrave) is 
to be taken with a high fat meal. 
In the pharmacotherapy group alone, dosing protocols will be followed for treatment of obesity: Orally, 1 
tablet (90mg/8mg) initially week 1; increase by 1 tablet/day each subsequent week until daily 
maintenance dose of 2 tablets twice daily (360 mg bupropion/32 mg naltrexone) is achieved at the start 
of week 4. Use will be discontinued at month 4 if no clinical response is observed. This drug (Contrave) is 
to be taken with a high fat meal. 
The IC control group will receive diet and physical activity information to encourage them to adopt 
healthier eating (limit HPFS/increase CC intake) and physical activity behaviors. IC information sessions 
will occur at the same time points as the intervention sessions (baseline, 1, 2,3, and 4 weeks and 2, 3, 4, 
5, and 6 months) and will be similar in length. The PI and co-PIs will develop information packets for each 
session, (self-management, avoiding highly processed LNSC foods, low intensity physical activity, 
avoiding highly processed fatty foods, medium intensity physical activity, avoiding LNSC beverages, 
importance of water as a beverage to hydrate and reduce cravings, avoiding high fat beverages, high 
intensity physical activity, importance of CC intake). 
 
Data Collection 
All research personnel will be CITI-trained. A nursing student will assist the nurse researchers with data 
collection. Each data collector will undergo fidelity checks (performed by the PI) for each measurement 
procedure before they will be allowed to collect data. They will also be trained in using the ASA24-2016® 
dietary recall, so they can assist the patients as needed. 
The current version of the YFAS, the YFAS 2.0, will be used to assess participants obesity phenotype 
(positive or negative for FA). This measure adapts the eleven DSM-5 diagnostic criteria for substance-
related and addictive disorders when the substance is HPFS foods. In order to meet the diagnostic 
threshold on the YFAS, individuals must report at least two of the eleven diagnostic indicators of FA plus 
clinically significant impairment or distress.  
 

The Automated Self-Administered 24-hour Recall, version ASA24-2016® will be completed at each time 
point to assess changes in patients dietary intake. This web-based 24-hour dietary recall instrument has 
been used effectively by hundreds of researchers and has face validity and similar intake results to the 
AMP.10 A strength of the ASA24-2016® is that it includes most traditional American foods/ingredients.  
Height: The patients height will be used in determining BMI and BIA measures. We will use the average 
of 2 heights (cm) measured with the Seca EC0123 stadiometer. During measurement, patients will be in 
socked feet with heels placed against the back of the platform and facing straight forward. 
Body Composition: Bioelectrical impedance analysis (BIA) will be used to determine body composition. 
Estimated standard error for BIA is ± 3.5-5%.  We will use a Tanita SC-250 body composition analyzer and 
follow a standardized protocol to measure percent body fat, body fat mass, fat free mass, percent body 
water, muscle mass, bone mass, BMI, and visceral fat. The software also classifies patients as underfat, 
healthy, overfat, or obese based on percent body fat, age and gender. 
Waist circumference: We will use the average of 2 measurements (cm) performed with the patient 
standing erect with their arms at their sides. Waist circumference will be measured at the uppermost 
lateral border of the right ilium at the end of normal expiration using an inelastic tape measure 
positioned around the trunk parallel to the floor. This measure is included because it is a better indicator 
of body fat and, therefore, health risk than 
BMI:  In addition, results of a recent study in this population demonstrated that waist circumference has 
potential as a means of identifying patients with or at risk for obesity and hypertension. 
Blood Pressure: We will use the average of 2 blood pressure measurements performed using an Omron 
HEM- 907 automatic blood pressure monitor. The measurements will be performed while the patient is 
quiet and still using the appropriate sized cuff placed snugly around the upper arm approximately 2 to 3 
cm above the antecubital fossa with the mark on the cuff aligned with the artery. 
Determinants of Change Measures: MI Algorithm Questions: These reflect the PCBT determinants of 
behavior change (the patients perceptions toward limiting HPFS/increasing CC intake). They assess 
patient attitudes/beliefs (importance score), perceived norms (perceived barriers), and perceived 
behavioral control/self-efficacy (confidence score). These measures will be recorded by the 
interventionist nurses during each MI session for their assigned patients. 
If a subject experiences success in managing their weight while participating in the study,(which will be 
determined by a 5% decrease in BMI or body fat or total body mass over 4 months) the subject may 
continue with the weight management plan after completing all study related visits. All participants may 
continue with clinic visits following the study and may have available to them, usual care, MI, Contrave 
(unless they have taken it in the study and it was not effective), and bariatric surgery options. All subjects 
taking Contrave will be screened at each visit for suicidal ideation. In addition, they will be asked to call 
Dr. Bowman immediately if they have any such feelings or symptoms of suicidal ideation. If they present 
with suicidal ideation, Dr. Bowman will interview them using the Suicide Screening Algorithm (see 
documents) to determine the severity of the symptoms and make additional medical referrals as 
necessary. If the case is emergent, they will be immediately escorted to the ER or asked to come into the 
ER, if it is a phone visit. . If the case is urgent, they will be referred to psychiatric personnel in the office 
where Dr. Bowman practices as a Psychiatric NP. They will be withdrawn from the study at this time and 

Dr. Aguirre will be notified. Dr. Bowman will follow up with these patients. At the six month visit a PHQ-9 
and the YFAS (from the WALI) will be readministered. An appt for a 12 month sustainability measure will 
be set up. 
 
Statistical Methods to Analyze Data 
Missing data will be evaluated. For summated scales on which fewer than 20% of an individuals 
responses are missing, the individuals mean on the remaining items may be substituted, as appropriate. 
For analyses requiring complete data, imputation of missing values using the EM algorithm or multiple 
imputations will be considered, as appropriate. Scoring algorithms for each instrument will be used per 
the published use manual. Each statistical test will be conducted at p=.05 level. Data will be analyzed 
using descriptives (means, medians, standard deviations of scores), independent t-tests, correlation 
coefficients and analysis of variance. In Aim 1, ANOVA will be used to assess differences between the 
three treatment groups on the YFAS to determined changes in MI confidence, importance and readiness 
to change scores as well as ASA24-2016® dietary recall and biometric measures. Correlational analysis 
will be used to explore the relationships between ASA24-2016® dietary recall and biometric measures. In 
Aim 2 independent t-test will be used to determine if the positive and negative YFAS groups differ across 
treatment responses.