Clinical trial NCT03779048
Conditions: Obesity
Keywords: phentermine Hypoglycemic agents Incretins Hormones Appetitive Behavior Appetite Depressants Anti-Obesity Agents Weight Loss Body Weight Body Weight Changes Signs and Symptoms
Sponsor: University of Pennsylvania
Start date: 2019-07-15; Completion date: 2022-05-25
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a two-phase study. Phase 1 will evaluate obesity-related behavioral and biological characteristics as potential predictors of response to behavioral treatment (BT) for weight loss. Phase 2 is a double-blind, placebo-controlled, RCT to test whether adding weight loss medication to BT improves 24-week weight loss, as compared to BT with placebo, in subjects identified as having suboptimal early weight loss after 4 weeks of individual behavioral weight control. All participants, regardless of their early weight loss, will receive the same BT program of diet, physical activity, and behavior therapy for weight loss for an additional 24 weeks (28 total weeks of treatment).

Detailed description:
Subjects will be a total of 150 adults, aged 21-70 years, with a body mass index (BMI) of 31 kg/m2 or above (28 kg/m2 with an obesity-related comorbidity). In phase 1, eligible subjects will complete questionnaires and an in-person baseline assessment of obesity-related behavioral characteristics (satiety, hunger, the relative reinforcing value of food \[RRVfood\], and impulsivity \[delay discounting\]), neuropeptides, and gastric emptying. After this baseline assessment, participants will begin an initial 4-week behavioral treatment (BT) "run-in" delivered individually in 20-30 minute weekly sessions (delivered virtually).

The primary goal of phase 1 will be to evaluate baseline satiety, postprandial change in GLP-1, and gastric emptying as predictors of percent weight loss after 4 weeks of BT. We will also examine whether these variables predict categorization as a suboptimal early responder to BT (e.g., \<2.0% loss; co-primary outcome).

Secondary endpoints of phase 1 are percent weight loss from the start of the BT run-in (week -4) to randomization (week 0) and categorization as a suboptimal early responder, as predicted by additional behavioral characteristics (hunger as measured by VAS ratings, RRVfood as measured using a computer task, and impulsivity as measured using a delay discounting computer task) and neuropeptides (higher fasting ghrelin, lower fasting leptin, and lower postprandial changes in insulin and PYY).

In phase 2, suboptimal early responders (based on weight loss during the BT run-in) will be randomly assigned to 24 weeks of: 1) BT plus placebo (BT+P); or 2) BT plus medication (BT+M; phentermine 15.0 mg). Both treatment groups will continue to attend 20-30 minute individual BT sessions (delivered virtually), weekly for the first 12 weeks and every other week for the last 12 weeks (total of 18 visits). Both treatment groups will also take once daily study medication (placebo or phentermine 15.0 mg) for the duration of the intervention period. Early BT responders identified during the run-in will receive the same 24-week BT program, but will not receive study medication or be included in the randomized trial.

The assessments administered at baseline - questionnaires, including behavioral testing, blood draws, and measurements of body weight - will be repeated at randomization (week 0) and at week 24.

The primary endpoint of phase 2 is change in body weight (i.e., % reduction in initial weight), as measured from randomization to week 24, among suboptimal early responders assigned to BT+P vs. BT+M. A randomized sample size of 50 non-responders (25 per group), assuming a 20% attrition rate, will give us 81.5% power to detect between-treatment group differences at week 24 of 4.5% (effect size: d = 0.82).

Secondary endpoints of phase 2 will include change in body weight in kg from randomization to week 24, as well as the portion of suboptimal early responders who achieve a post-randomization loss of ≥ 5% and ≥ 10% of initial body weight. We will also examine differences between suboptimal early responders treated with BT+M vs. BT+P in changes in hunger, satiety, the reinforcing efficacy of food, and impulsivity between randomization and week 24. A comparison will also be made in percent weight loss from randomization to week 24 between suboptimal early responders treated with BT+M and early responders treated with BT alone.

If you are interested in participating in this study, information and a link to contact the research team can be found here: https://clinicalresearch.itmat.upenn.edu/3XOX/ or you can call us at the numbers listed below.

Arms: arm 1: Participants with suboptimal early weight loss in the BT run-in will then be randomly assigned to 24 additional weeks of: 1) BT plus placebo (BT+P); or 2) BT plus medication (BT+M; phentermine 15.0 mg) in a double-blinded fashion. Both treatment groups will continue to attend individual BT sessions and will take a once daily study medication (placebo or phentermine 15.0 mg) for the duration of the intervention period.

Early BT responders identified during the run-in will receive the same 24-week BT program, but will not receive study medication or be included in the randomized trial. arm 2: Participants with suboptimal early weight loss in the BT run-in will then be randomly assigned to 24 additional weeks of: 1) BT plus placebo (BT+P); or 2) BT plus medication (BT+M; phentermine 15.0 mg) in a double-blinded fashion. Both treatment groups will continue to attend individual BT sessions and will take a once daily study medication (placebo or phentermine 15.0 mg) for the duration of the intervention period.

Early BT responders identified during the run-in will receive the same 24-week BT program, but will not receive study medication or be included in the randomized trial. arm 3: All enrolled participants will complete an initial 4-week behavioral treatment (BT) run-in. This run-in will be used to identify early non-responders to BT, defined by a weight loss \<2% of initial weight after 4 weeks of BT. Early responders are those who lose \>=2%.

Only early non-responders will then be enrolled in the randomized trial.
Interventions: intervention 1: Behavioral Treatment intervention 2: Placebo intervention 3: Phentermine 15 MG
Intervention descriptions: intervention 1: Behavioral treatment (BT) for weight loss includes diet and physical activity recommendations and behavior therapy strategies. All participants will complete an initial 4-week BT run-in, delivered in individual, 20-30 minute weekly sessions. After the end of the run-in, participants will be offered an additional 24 weeks of 20-30 minute individual BT sessions, occurring weekly for the first 12 weeks and every other week for the last 12 weeks (total of 18 visits). intervention 2: The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill. intervention 3: The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill.

Protocol documents:
Prot_SAP_000.pdf: 
   
 
 
 
USE OF PHARMACOTHERAPY TO IMPROVE WEIGHT LOSS 
IN EARLY NON-RESPONDERS TO BEHAVIORAL 
TREATMENT 
 
 
 
 
Principal Investigator (1) 
Jena Shaw Tronieri, PhD 
Department of Psychiatry 
Perelman School of Medicine, University of Pennsylvania 
3535 Market St., Ste. 3025 
Philadelphia, PA 19104 
Phone: 215-746-5045 
Jena.Tronieri@pennmedicine.upenn.edu 
 
Co-Investigators 
Thomas A. Wadden, Ph.D. 
Robert Berkowitz, M.D.  
 
 
 
Tanja Kral, Ph.D. 
 
Investigational Product: 
 
Phentermine 15.0 mg  
Protocol Number: 
 
 
IRB Number: 
Application number 1K23KD116935-01A1  
 
 
 
IND/ IDE Number: 
Not applicable 
 
 
 
ClinicalTrials.gov Number       
 
 
 
NCT03779048  
Universal Trial Number (UTN): U1111-1198-6481 
 
 
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Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS ....................................................................................................................... IV 
STUDY SUMMARY ..................................................................................................................................... 1 
KEY INCLUSION CRITERIA ........................................................................................................................... 3 
KEY EXCLUSION CRITERIA .......................................................................................................................... 3 
BACKGROUND AND STUDY RATIONALE .............................................................................................. 6 
INTRODUCTION .......................................................................................................................................... 6 
1.1 
BACKGROUND AND RELEVANT LITERATURE ........................................................................................ 6 
1.2 
TREATING BT NON-RESPONDERS. ..................................................................................................... 7 
2 
STUDY OBJECTIVES ........................................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE OF PHASE 1 ...................................................................................................... 8 
2.2 
SECONDARY OBJECTIVES OF PHASE 1 ............................................................................................... 8 
2.3 
PRIMARY OBJECTIVE OF PHASE 2 ...................................................................................................... 8 
2.4 
SECONDARY OBJECTIVES OF PHASE 2 ............................................................................................... 8 
3 
INVESTIGATIONAL PLAN ................................................................................................................... 9 
3.1 
GENERAL DESIGN ............................................................................................................................. 9 
3.2 
ALLOCATION TO INTERVENTIONAL GROUP .......................................................................................... 9 
3.3 
STUDY ENDPOINTS ......................................................................................................................... 10 
3.3.1 
Primary Study Endpoints ...................................................................................................... 10 
3.3.2 
Secondary Study Endpoints ................................................................................................. 10 
3.3.3 
Exploratory Endpoints ........................................................................................................... 10 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 11 
4.1 
INCLUSION CRITERIA ....................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 11 
4.3 
RANDOMIZATION CRITERIA .............................................................................................................. 12 
4.4 
SUBJECT RECRUITMENT ................................................................................................................. 12 
4.5 
DURATION OF STUDY PARTICIPATION .............................................................................................. 12 
4.6 
TOTAL NUMBER OF SUBJECTS AND SITES ........................................................................................ 12 
4.7 
VULNERABLE POPULATIONS: ........................................................................................................... 12 
5 
STUDY INTERVENTIONS .................................................................................................................. 12 
5.1 
BT RUN-IN ..................................................................................................................................... 12 
5.2 
BT INTERVENTION .......................................................................................................................... 13 
5.3 
MEDICATION AND PLACEBO INTERVENTIONS .................................................................................... 13 
5.4 
PREPARATION AND PACKAGING OF STUDY MEDICATIONS .................................................................. 13 
5.5 
MEDICATION STORAGE ................................................................................................................... 13 
5.6 
BLINDING ....................................................................................................................................... 14 
5.7 
ADMINISTRATION AND ACCOUNTABILITY ........................................................................................... 14 
5.8 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 14 
6 
STUDY PROCEDURES ...................................................................................................................... 15 
7.1 
SCREENING PROCEDURES .............................................................................................................. 17 
7.2 
RANDOMIZATION VISIT .................................................................................................................... 17 
7.3 
OUTCOME ASSESSMENTS ............................................................................................................... 17 
7.4 
TREATMENT VISITS ......................................................................................................................... 17 
7.5 
MISSED VISITS ............................................................................................................................... 18 
7.6 
SUBJECT WITHDRAWAL .................................................................................................................. 18 


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7.7 
EARLY TERMINATION VISITS ............................................................................................................ 18 
8 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................. 18 
8.1 
PRIMARY OUTCOME MEASURE: BODY WEIGHT ................................................................................ 19 
8.2 
PHASE 1 PREDICTOR VARIABLES ..................................................................................................... 19 
8.2.1 
APPETITE, NEUROPEPTIDES, AND GASTRIC EMPTYING ................................................................... 19 
8.2.2 
IMPULSIVITY ................................................................................................................................ 19 
8.2.3 
RELATIVE REINFORCING VALUE OF FOOD ..................................................................................... 19 
8.3 
CARDIOMETABOLIC RISK ................................................................................................................. 20 
8.4 
QUESTIONNAIRE MEASURES ........................................................................................................... 20 
9 
STATISTICAL PLAN .......................................................................................................................... 20 
9.1 
SAMPLE SIZE AND POWER DETERMINATION ..................................................................................... 20 
9.2 
STATISTICAL METHODS ................................................................................................................... 21 
9.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 22 
10 
SAFETY AND ADVERSE EVENTS .................................................................................................. 23 
10.1 
DEFINITIONS ................................................................................................................................ 23 
10.1.1 
Adverse Event .................................................................................................................... 23 
10.1.2 
Serious Adverse Event ....................................................................................................... 23 
10.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 23 
10.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 24 
10.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................................ 24 
10.4.1 
Follow-up report .................................................................................................................. 24 
10.5 
UNBLINDING PROCEDURES ........................................................................................................... 25 
10.6 
MEDICAL MONITORING .................................................................................................................. 25 
10.6.1 
Data and Safety Monitoring Plan ........................................................................................ 26 
11 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 27 
11.1 
CONFIDENTIALITY ......................................................................................................................... 27 
11.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 27 
11.3 
RECORDS RETENTION .................................................................................................................. 28 
12 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 28 
13 
ETHICAL CONSIDERATIONS ......................................................................................................... 28 
13.1 
RISKS .......................................................................................................................................... 29 
13.2 
BENEFITS ..................................................................................................................................... 31 
13.3 
RISK BENEFIT ASSESSMENT .......................................................................................................... 32 
13.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ............................................................... 32 
14 
STUDY FINANCES ........................................................................................................................... 32 
14.1 
FUNDING SOURCE ........................................................................................................................ 32 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 32 
14.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 32 
15 
PUBLICATION PLAN ....................................................................................................................... 32 
16 
REFERENCES .................................................................................................................................. 32 
17 
ATTACHMENTS ............................................................................................................................... 39 
 
 
 
 
 
 


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List of Abbreviations 
 
AE: Adverse event 
BMI: Body mass index 
BT: Behavioral treatment for obesity 
BT + M: Behavioral treatment plus medication with phentermine 15.0 mg 
BT + P: Behavioral treatment plus placebo 
CMP: Comprehensive metabolic panel 
GLP-1: Glucagon-like-peptide-1 
IDS: Investigational Drug Service (at Penn) 
NP: Nurse practitioner 
PYY: Peptide YY 
RD: Registered dietitian  
RRVfood: Relative reinforcing value of food 
SAE: Serious adverse event 
 
 
 
 
 
 


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Study Summary 
Title 
Use of Pharmacotherapy to Improve Weight Loss in Early Non-responders to 
Behavioral Treatment 
Short Title 
Medication in BT Non-responders 
IRB Number 
 
Phase 
N/A 
Methodology 
Double blind, placebo-controlled randomized trial 
Study Duration 
4 years  
Study Center(s) 
Single-center  


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Objectives 
Primary: 
• 
Phase 1: To characterize satiety in early non-responders to 
behavioral treatment (BT). Lower satiety ratings, lower postprandial 
increases in GLP-1, and more rapid gastric emptying at baseline are 
hypothesized to predict percent weight loss from the start of the BT 
run-in (week -4) to randomization (week 0), as well as categorization 
as an early non-responder who lost < 2.0% of initial weight at 
randomization (co-primary outcomes). 
 
• 
Phase 2: To test the effect of augmenting BT with the weight loss 
medication phentermine 15.0 mg (BT+M), compared to BT plus 
placebo (BT+P), on weight loss in early non-responders who lose < 
2.0% of initial weight during a 4-week behavioral run-in. Percent 
weight loss from randomization to week 24 is the study’s primary 
endpoint. 
 
Secondary: 
• 
Phase 1: To examine whether additional behavioral characteristics 
(higher fasting hunger, relative reinforcing value of food [RRVfood], 
and impulsivity) and neuropeptides (higher fasting ghrelin, lower 
fasting leptin, and lower postprandial changes in cholecystokinin and 
peptide YY) predict 4-week weight loss, as well as categorization as 
a non-responder during the BT run-in. 
 
• 
To compare the portion of early non-responders who achieve a post-
randomization loss of ³ 5% and ³ 10% of initial body weight with 
BT+M and BT+P.  
 
• 
To compare non-responders treated with BT+M vs. BT+P in changes 
in hunger, satiety, RRVfood, and impulsivity between randomization 
and week 24.  
 
• 
To explore differences in percent weight loss from randomization to 
week 24 between early non-responders treated with BT+M and early 
responders treated with BT alone. 
Number of Subjects 
150 subjects (180 in-person screenings to obtain 150) 
60 subjects randomized to study medication(s) 


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Main Inclusion and 
Exclusion Criteria 
Key Inclusion Criteria 
1. BMI ≥ 31 kg/m² (or 28 kg/m2 with obesity-related comorbidity)  
2. Age ≥ 21 years and ≤ 70 years  
3. Has a primary care provider (PCP) responsible for providing routine care 
4. Plans to remain in the Philadelphia area for the next 9 months or more 
Key Exclusion Criteria 
5. Pregnant or nursing, or plans to become pregnant in the next 9 months. 
6. Uncontrolled hypertension (systolic blood pressure ≥ 140 mm Hg or 
diastolic blood pressure ≥ 90 mm Hg) 
7. Type 1 diabetes 
8. Type 2 diabetes 
9. A fasting blood glucose > 126 mg/dL(on second assessment after first 
elevated value, patients are excluded if they have both fasting blood 
glucose > 126 mg/dL and HbA1c ≥ 6.5)  
10. History of cardiovascular disease (e.g., coronary artery disease, stroke, 
arrhythmias, congestive heart failure, or heart block greater than first 
degree) 
11. Clinically significant hepatic or renal disease 
12. Hyperthyroidism 
13. Other thyroid disease, not controlled. 
14. History of malignancy (except for non-melanoma skin cancer) in past 5 
years 
15. Narrow angle glaucoma 
16. Presence or history of marked agitation 
17. Current severe major depressive episode (BDI-II score ≥ 29), current 
active suicidal ideation, or history of suicide attempts within the past 5 
years. 
18. Any severity of thought or bipolar disorder, or bulimia nervosa. 
19. Psychiatric hospitalization within the past 6 months 
20. Self-reported alcohol or substance abuse within the past 6 months, 
including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per 
week) 
21. Past year history of drug abuse. 
22. Use in the past 2 weeks of monoamine oxidase inhibitors. 
23. Current use of serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., 
venlafaxine, duloxetine, desvenlafaxine, milnacipran, levomilnacipran).  
24. Use in past 6 months of medications known to induce significant weight 
loss (e.g., prescription weight loss medications) or weight gain (e.g., 
chronic use of oral steroids, second generation antipsychotics) 
25. Loss of ≥ 5% of initial body weight within the past 6 months 
26. History of (or plans for) bariatric surgery (e.g., roux en y gastric bypass, 
sleeve gastrectomy, gastric banding), endoscopic intragastric balloon, or 
aspire assist.  
27. Inability to walk 5 blocks comfortably or engage in some other form of 
aerobic activity (e.g., swimming) 
28. Known or suspected allergy to sympathomimetic amines or related 
products 
29. The receipt of any investigational drug within 6 months prior to this trial 
30. Previous participation in this trial (e.g., randomized and failed to 
participate) 
31. Changes to any chronic medication (type or dosage) within the past 3 
months. 


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32. Any serious or unstable medical or psychological condition that, in the 
opinion of the investigator, would compromise the patient’s safety or 
successful participation in the study 
Investigational 
Product (drug, 
biologic, device, etc.) 
For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
Phentermine 15.0 mg/day, provided in capsule form. (Study medication will 
be initiated at 8.0 mg/day for the first 2 weeks and increased to 15.0 mg/day 
thereafter.) 
Duration of 
administration (if 
applicable) 
24 weeks 
Reference therapy 
Placebo for phentermine 
Statistical 
Methodology 
All data will be analyzed under the intention-to-treat principle. Multiple 
regression and discriminant analysis will be used to examine phase 1 
predictors of early weight loss with BT and categorization as a non-
responder, respectively. To assess the primary phase 2 outcome of percent 
weight change by treatment group (among non-responders), a mixed effects 
model will be fit with treatment group (BT+P, BT+M) as a between-subjects 
factor and time (week) as a within-subjects factor to estimate and test group 
differences at week 24 (primary endpoint).  
Safety Evaluations  
 
 
Safety endpoints include physical examination, adverse events (AEs), and 
standard laboratory tests. In addition to assessment visits, randomized 
subjects will have a brief medical monitoring visit (10-15 minutes) with study 
staff (e.g., registered nurse) at week 2 (after initiation of the medication) and 
week 4 (after most subjects will have completed dose escalation) to monitor 
response to the medication. Study subjects will be asked whether there has 
been any change in their health or medications.  
 
Side effects will be queried during every study visit, and the study NP or 
physician will be available to assess the subject and evaluate and treat any 
adverse events. Subjects will be encouraged to contact study staff immediately 
should an AE occur between visits, and 24-hour contact information will be 
provided for study personnel and the study physician. If any AE requires 
treatment follow-up, subjects will be provided with appropriate referrals. 
 
Subjects will have fasting blood draws (comprehensive metabolic panel [CMP] 
and lipids) at screening, and at randomization and week 24. Vital signs (blood 
pressure and pulse) will be measured at screening and post-randomization 
weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24.  
 


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Data and Safety 
Monitoring Plan  
The principal investigator (PI, Dr. Tronieri) will be responsible for overseeing 
and monitoring the study. Safety and data quality monitoring will be 
performed on an ongoing basis by the PI and research coordinator, in 
consultation with Drs. Wadden and Berkowitz. 
 
A Safety Monitoring Committee consisting of a safety officer and data officer 
will provide additional study oversight. This team will include at least one 
external (non-Center) reviewer. The Committee will be responsible for 
executing the data safety and monitoring plan, monitoring trial safety and 
efficacy, and complying with Public Health Service reporting requirements. 
This team will meet prior to the start of recruitment to review the protocol, 
human subjects’ protections, and plans for data and safety monitoring. They 
will then meet twice per year to review the study’s progress and de-identified 
group-level data for differential rates in AEs and key outcomes 
 
 
 


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BACKGROUND AND STUDY RATIONALE 
This study will be conducted in compliance with the protocol and in full accordance with Good Clinical 
Practice standards, all applicable University of Pennsylvania Research Policies and Procedures, and all 
applicable Federal and state laws and regulations including 45 CFR 46, 21 CFR Parts 50, 54, and 56. 
Introduction 
A substantial minority of patients treated with behavioral treatment (BT) for obesity fail to achieve clinically 
meaningful losses of ≥ 5% of initial weight. Medications approved by the Food and Drug Administration 
(FDA) for weight management enhance average weight losses when combined with BT; however, their use 
among patients with suboptimal response to BT has never been tested in a randomized controlled trial. 
This study seeks to identify behavioral and biological phenotypes predictive of poor response to BT and 
test whether providing pharmacotherapy with phentermine 15.0, as compared to placebo, improves the 
induction of weight loss for subjects who lose minimal weight with 4 weeks of BT alone (a strong predictor 
of later failure to lose ≥ 5% of initial weight with that treatment). 
1.1 
Background and Relevant Literature  
 
1.1.1 
Obesity and Its Treatment. 
 
Obesity, defined by a BMI ≥ 30 kg/m², is the most common nutritional disease in the United States, affecting 
about 36% of adults age 20 years and over. An additional 33% of American adults are overweight, as 
judged by a BMI of 25.0-29.9 kg/m². Obesity is associated with a number of co-morbidities including type 2 
diabetes (70% of people with type 2 diabetes are obese) and cardiovascular disease.  
Current treatment guidelines e.g., 1 recommend that patients with obesity be offered comprehensive 
behavioral treatment that includes a reduced calorie diet, increased physical activity, and behavioral 
strategies to facilitate adherence to diet and activity goals. On average, patients achieve losses of 5-8% of 
initial weight with 6 months of high intensity BT (i.e., ≥ 14 individual or group sessions in 6 months). 1 
(Providing more than 16 visits in 6 months [e.g., weekly visits] does not appear to significantly increase 
weight loss. 2) A loss of ³ 5% of initial weight is commonly used as a criterion for clinically meaningful weight 
loss and is associated with improvements in cardiometabolic risk factors. 3 However, 35-50% of patients 
fail to lose this amount in high intensity BT programs. 4, 5 
 
1.1.2 
Non-response to BT. 
 
Numerous studies have shown that slow early weight loss (e.g., < 0.5% of body weight per week) in the 
first 1-2 months of BT is a strong predictor of limited total weight loss after 6-12 months of treatment. 4, 6-13 
Approximately one third of participants fail to lose ³ 0.5% of body weight per week in the first month of BT, 
and the majority of these early non-responders do not achieve a loss of ³ 5% body weight after 6 months 
of treatment (53-70%).4, 7, 8 
 
1.1.3 
Factors Influencing Weight Loss Success. 
 
Obesity-related phenotypes, consisting of clusters of behavioral, psychological, and physiological 
characteristics, may facilitate or limit response to BT.14, 15 The most consistent behavioral phenotypes 
associated with poor weight loss include low satiety and high hunger, 16-19 as well as a high reinforcing 
value of food 20, 21 and high impulsivity. 21-26 Lower satiety ratings after consuming a standard meal predict 
higher short- and long-term energy intake and less weight loss with BT. e.g. 16, 17, 27 Higher fasting hunger 
has also been associated with greater energy intake and poor weight loss 16, 18, 19. A high relative reinforcing 
value of food (RRVfood) is associated with higher food intake and body weight. 27-31 Delay discounting (DD) 
is conceptualized as an aspect of impulsivity that reflects difficulty with inhibiting responses to rewarding 
stimuli.24, 28, 32 In a meta-analysis, individuals with a steeper rate of DD, or those with the greatest preference 
for immediate rewards over larger, delayed rewards, were more prone to obesity.24 Individuals who have 
both a high RRVfood and steep DD may have the greatest difficulty regulating their intake in order to lose 


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weight,21, 28, 32-34 because weight loss participants are asked repeatedly to choose low-calorie foods that will 
produce long-term weight loss over palatable high-calorie foods that offer a more immediate reward.26, 28  
Behavioral phenotypes are presumed to be linked to biological mechanisms that control hunger and 
food responsiveness. 20, 26, 35-38 Several neuropeptides are involved in the detection of long- (e.g., leptin) 
and short-term energy needs (e.g., glucagon-like-peptide-1 [GLP-1], ghrelin, insulin, peptide YY [PYY]), 
and they influence perceived palatability and reward-motivated eating (e.g., GLP-1, leptin, ghrelin). e.g. 39, 
40 The rate of gastric emptying both influences and is influenced by several of these neuropeptides and 
may also affect food consumption and body weight.39, 41-43 However, few studies have examined whether 
pre-treatment neuropeptide levels or gastric emptying predict weight loss with BT. The majority of these 
studies have examined the role of pre-treatment leptin and ghrelin levels in predicting weight loss, with 
mixed success.39, 44-49 
Individual predictors typically explain only a small amount of the variance in weight loss outcomes, 
suggesting high inter-individual variability in mechanisms of non-response.50 In some cases, obesity 
phenotypes may be mutually exclusive (e.g., high hunger and low satiety), while in others, the combination 
of several traits may best characterize a mechanism of non-response (e.g., high RRVfood and high 
impulsivity). The ability of most studies to detect distinct phenotypes that predict weight loss has been 
limited by their inclusion of only a small number of self-report measures.14, 50, 51 Simultaneously examining 
multiple behavioral traits using laboratory-based assessments, along with neuroendocrine biomarkers and 
gastric emptying, may enhance our ability to identify phenotypes associated with poor response to BT. 
Better characterizing these non-responders will in turn facilitate the development of tailored treatments that 
can address different biopsychosocial barriers.  
1.2 
Treating BT Non-responders. 
 
In addition to identifying mechanisms of non-response, it is important to evaluate whether alternative 
treatments improve the weight losses of BT non-responders. Several researchers have recommended that 
non-responders be provided with a different treatment method as early as possible, rather than spending ³ 
6 months in a treatment program that is unlikely to facilitate a clinically significant weight loss. 4, 6-9 Early 
non-responders to BT are also likely to become discouraged about reaching their desired weight loss goals 
and are more likely to drop out of treatment. 10, 52, 53 
Several studies have examined the efficacy of stepped-care approaches in which BT is intensified for 
patients who do not meet early weight loss milestones. The baseline treatment offered in these programs 
has been of low intensity, consisting of self-help 54, internet-based BT 55, or monthly BT visits 56, and 
treatment has primarily been intensified by increasing provider contact. The effect of offering a categorically 
different treatment to early non-responders in an intensive BT program has not been tested in an RCT. 
 
1.2.1 
Pharmacotherapy for Weight Management. 
 
Expert panels recommend that individuals with a BMI ³ 30 kg/m2 (or BMI ³ 27 kg/m2 with comorbidity) 
be offered adjunctive treatments such as FDA-approved medications for chronic weight management if 
they are unable to lose weight or sustain weight loss with BT alone. 1, 57 Multiple studies have demonstrated 
that combining BT with medication produces greater weight loss (and reduces weight regain), compared to 
BT with placebo. e.g., 58-68 Wadden and colleagues 59 have shown that the effects of BT and medication are 
additive. Participants prescribed medication alone (sibutramine 10-15 mg/day) lost 5 kg of initial weight at 
1 year, those provided high-intensity BT alone lost 6.7 kg, and those given the combination of these two 
therapies lost 12.1 kg. 59  
 
Phentermine 15.0 mg. 
 
Phentermine hydrochloride is a sympathomimetic amine thought to reduce appetite and food intake by 
increasing norepinephrine and possibly catacholamine levels in the hypothalamus. Phentermine was 
approved by the Food and Drug Administration (FDA) in 1959 for “short-term” use, commonly interpreted 
as 12 or fewer weeks. In 2012, the FDA approved the combination of phentermine (7.5 – 15.0 mg/d) plus 
topiramate for long-term weight management (e.g., ≥12 months). Phentermine (monotherapy) is the most 
widely used weight loss medication in the U.S. and is frequently prescribed in clinical practice for periods 


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longer than 12 weeks. 69-71 The FDA did not require an Investigational New Drug (IND) application for the 
use of phentermine in the present study. Patients without diabetes achieve average placebo-subtracted 
weight losses of 4.0 to 7.4 kg with 12 to 28 weeks of treatment with phentermine (15.0-30.0 mg/d). 72-77 In 
a recent representative study, subjects who received BT plus phentermine 15.0 mg/d lost 6.0 kg (6.1% of 
initial weight), whereas those who received BT with placebo lost 1.5 kg (1.7% of initial weight). 77  
Higher fasting hunger and lower dietary restraint have been shown to predict a greater likelihood of 
achieving a 5% weight loss among patients treated with 8 weeks of phentermine. 18 In another study, low 
satiety was associated with reduced weight loss at 2 weeks in patients assigned to placebo, but with greater 
weight loss in those who received phentermine-topiramate. 78 These findings suggests that phentermine 
will be particularly beneficial for individuals with the very phenotypes (e.g., high hunger, low satiety) that 
may predict non-response to BT. 
Studies of the efficacy of weight loss medication have either initiated medication simultaneously with 
low- to moderate-intensity BT, 61, 63-65, 68 or have only randomized patients to medication or placebo if they 
succeeded in achieving a certain weight loss criterion (e.g., 5%) during an initial BT run-in. 58, 66, 67, 79 
Remarkably, the recommendation to offer weight loss medication to individuals who are unable to 
successfully lose weight with BT alone has not been tested.  
2 
Study Objectives 
This study consists of two phases. Phase 1 will evaluate obesity-related behavioral and biological 
characteristics as potential mechanisms of non-response to BT. Phase 2 is a double-blind, placebo-
controlled, RCT to test whether augmenting BT with weight loss medication improves 6-month weight loss, 
as compared to BT with placebo, in subjects identified as early non-responders to 4 weeks of individual 
behavioral weight control.  
2.1 
Primary Objective of Phase 1 
• 
To characterize satiety in early non-responders to behavioral treatment. Lower satiety ratings, 
lower postprandial increases in GLP-1, and more rapid gastric emptying at baseline are 
hypothesized to predict percent weight loss from the start of the BT run-in (week -4) to 
randomization (week 0), as well as categorization as an early non-responder who lost < 2.0% of 
initial weight at randomization (co-primary outcomes). 
2.2 
Secondary Objectives of Phase 1 
• 
To examine whether additional behavioral characteristics (higher fasting hunger, relative 
reinforcing value of food [RRVfood], and impulsivity) and neuropeptides (higher fasting ghrelin, 
lower fasting leptin, and lower postprandial changes in insulin and PYY) predict 4-week weight 
loss, as well as categorization as a non-responder during the BT run-in. 
2.3 
Primary Objective of Phase 2 
• 
To test the effect of augmenting BT with the weight loss medication phentermine 15.0 mg 
(BT+M), compared to BT plus placebo (BT+P), on weight loss in early non-responders who lose < 
2.0% of initial weight during a 4-week BT run-in. Percent weight loss from randomization to week 
24 is the study’s primary endpoint. 
2.4 
Secondary Objectives of Phase 2 
• 
To compare early non-responders treated with BT+M and BT+P on weight loss in kg from 
randomization to week 24. 
 
• 
To compare the portion of early non-responders who achieve a post-randomization loss of ³ 5% 
and ³ 10% of initial body weight with BT+M and BT+P.  
 
• 
To compare non-responders treated with BT+M vs. BT+P in changes in hunger, satiety, relative 
reinforcing efficacy of food, and impulsivity between randomization and week 24.  
 


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• 
To explore differences in percent weight loss from randomization to week 24 between early non-
responders treated with BT+M and early responders treated with BT alone.  
3 
Investigational Plan  
3.1 
General Design 
This is a two-phase study. Phase 1 will evaluate obesity-related behavioral and biological characteristics 
as potential mechanisms of non-response to BT. Phase 2 is a double-blind, placebo-controlled, RCT to test 
whether augmenting BT with weight loss medication improves 24-week weight loss, as compared to BT 
with placebo, in subjects identified as early non-responders to 4 weeks of individual behavioral weight 
control. Subjects will be a total of 150 adults, aged 21-70 years, with a body mass index (BMI) of 31 kg/m2 
or above (28 kg/m2 with an obesity-related comorbidity). Subjects will attend a screening visit in which they 
will complete a behavioral evaluation with a psychologist and a medical history. In phase 1, eligible subjects 
will complete questionnaires and an in-person baseline assessment of obesity-related behavioral 
characteristics (satiety, hunger, RRVfood, and impulsivity), neuropeptides, and gastric emptying. Within 2 
weeks of this assessment, they will begin an initial 4-week BT “run-in” delivered individually in 20-30 minute 
sessions. The primary goal of phase 1 will be to evaluate baseline postprandial satiety, postprandial change 
in GLP-1, and gastric emptying as predictors of early weight loss after 4 weeks of BT. We will also examine 
whether these variables predict categorization as an early non-responder to BT who loses < 2.0% of initial 
weight (vs. early responders who lose ³ 2.0%; approximately 33% vs. 66% of the sample, respectively). 
In phase 2, early non-responders (who lost < 2.0% during the BT run-in) will be randomly assigned to 
24 weeks of: 1) BT plus placebo (BT+P); or 2) BT plus medication (BT+M; phentermine 15.0 mg). Both 
treatment groups will continue to attend 20-30 minute individual BT sessions, weekly for the first 12 weeks 
and every other week for the last 12 weeks (total of 18 visits). Both treatment groups will also take once 
daily study medication (placebo or phentermine 15.0 mg) for the duration of the intervention period (with 
titration between randomization and week 2). Early BT responders identified during the run-in will receive 
the same 24-week BT program, but will not receive study medication or be included in the randomized trial. 
The assessments administered at baseline – questionnaires, including behavioral testing, blood draws, and 
measurements of body weight – will be repeated at randomization (week 0) and at week 24. 
Comment. The use in phase 2 of an adaptive design, in which hypotheses only include participants 
who do not lose ³ 2% with 4 weeks of BT, minimizes the size of the randomized sample treated in the 
current study. However, the initial sample size of 150 participants needed to assess weight loss predictors 
and identify at least 50 early non-responders is large for a K23 award. To limit treatment burden, we 
considered offering early responders no further treatment or a less intensive intervention following the 4-
week diet run-in. However, we thought that offering responders a low-intensity treatment (or no treatment), 
which is known to produce suboptimal weight loss,1 would not be ethical, and that doing so also would likely 
de-incentivize success during the 4-week run-in. We therefore decided to offer the same 24-week BT 
program to all participants who complete the run-in, regardless of responder status. Continuing to treat 
responders also allows us to conduct an exploratory analysis comparing the weight losses of these 
individuals to non-responders treated with BT + M. We also considered enrolling both early non-responders 
and early responders in the RCT. However, in consultation with program officers at NIDDK, we ultimately 
decided that it would be inappropriate to expose individuals to drug who were already successful with BT 
alone. Although we believe that the selected design provides the best balance between maintaining focus 
on the study’s primary aim of improving treatment for early non-responders and the ethical care of all 
enrolled participants, the ongoing treatment of responders with BT limits our ability to recruit a larger initial 
sample with the aim of powering the study with enough non-responders to test secondary aims.  
3.2 
Allocation to Interventional Group  
After completing 4 weeks of BT, subjects will attend a randomization visit (described to subjects as a 
“progress assessment visit”) at which their weight will be measured, and they will be categorized as an 
early non-responder (loss of < 2.0% of initial weight) or early responder (loss of ³ 2.0%). After early non-
responders’ eligibility is confirmed via a medical assessment, they will be randomly assigned in a 1:1 ratio, 
in randomly permuted blocks of 2 to 4 subjects, to one of the two treatment conditions. To maintain 
investigator blinding, randomization will be carried out by Penn’s Investigational Drug Services who will 


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purchase phentermine and package the study medications (phentermine or placebo) in blinded capsules. 
The first subject to meet the randomization criteria will be assigned the first number in the sequence; each 
subsequent subject to meet randomization criteria will be assigned the next number in the sequence. 
3.3 
Study Endpoints  
3.3.1 
Primary Study Endpoints 
The primary endpoints of phase 1 are percent weight loss from the start of the BT run-in (week -4) to 
randomization (week 0), as well as categorization as an early non-responder who lost < 2.0% of initial 
weight at randomization (co-primary outcomes), as predicted by postprandial satiety ratings (measured by 
visual analogue scales (VAS) during a test meal), postprandial change in GLP-1, and gastric emptying 
(measured using an acetaminophen test) at baseline. 
 
The primary endpoint of phase 2 is change in body weight (i.e., % reduction in initial weight), as 
measured from randomization to week 24. 
3.3.2 
Secondary Study Endpoints 
Secondary endpoints of phase 1 are percent weight loss from the start of the BT run-in (week -4) to 
randomization (week 0) and categorization as an early non-responder who lost < 2.0% of initial weight at 
randomization, as predicted by additional behavioral characteristics (hunger as measured by VAS ratings, 
RRVfood as measured using a computer task, and impulsivity as measured using a delay discounting 
computer task) and neuropeptides (higher fasting ghrelin, lower fasting leptin, and lower postprandial 
changes in insulin and PYY). 
 
Secondary endpoints of phase 2 will include change in body weight in kg from randomization to week 24, 
as well as the portion of early non-responders who achieve a post-randomization loss of ³ 5% and ³ 10% 
of initial body weight. We will also examine differences between non-responders treated with BT+M vs. 
BT+P in changes in hunger, satiety, the reinforcing efficacy of food, and impulsivity (measured as 
described above) between randomization and week 24. The groups also will be compared on changes in 
past week VAS ratings of hunger, fullness, food preoccupation, food liking, and cravings as measured at 
treatment visits. A comparison will also be made in percent weight loss from randomization to week 24 
between early non-responders treated with BT+M and early responders treated with BT alone.  
3.3.3 
Exploratory Endpoints 
An exploratory analysis will compare the two randomized groups (BT+M vs. BT+P) on changes from 
randomization to week 24 in CVD risk factors (i.e., blood pressure, triglycerides, LDL and HDL cholesterol, 
and waist circumference), glycemic control (i.e., fasting blood sugar), quality of life (as measured by the 
Short Form Health Survey (SF-36), mood (as measured by the Patient Health Questionnaire (PHQ-9)), and 
physical activity (Paffenbarger Physical Activity Questionnaire).  
An exploratory factor analysis will be used to determine whether primary and secondary predictor 
variables cluster into phenotypes. Exploratory endpoints will also include additional potential predictors of 
early response to BT. These will include measures of hunger (i.e., Eating Inventory [EI], past-week visual 
analogue scale [VAS] ratings), RRVfood (i.e., Power of Food Scale [PFS]), the reinforcing efficacy of food, 
general sensitivity to reward (i.e., the Behavioral Inhibition/Activation Scale [BIS/BAS]), impulsivity (i.e., the 
Barratt Impulsiveness Scale [BIS-15]), appetite (past-week VAS ratings), cognitive restraint (EI), 
disinhibition (EI), binge eating (i.e. the Questionnaire on Eating and Weight Patterns [QEWP-5]), food 
craving (i.e., Food Craving Questionnaire – Trait – reduced [FCQ-Tr]), emotional eating (Dutch Eating 
Behaviour Questionnaire [DEBQ]), perceived barriers to healthy eating and physical activity, diet and 
exercise self-efficacy (i.e., Weight Efficacy Life-Style Questionnaire [WEL], SCI Exercise Self Efficacy Scale 
[ESES]), social support for healthy eating and physical activity (i.e., Ball and Crawford Social Support 
Scale), hours of sleep per week, mindfulness and acceptance (Philadelphia Mindfulness Questionnaire 
[PHLMS]), food addiction (Yale Food Addiction Scale [YFAS]), indicators of withdrawal (Highly Processed 
Food Withdrawal Scale [ProWS]), perceived stress (i.e., Perceived Stress Scale), anxiety (i.e., GAD-7), and 
mood (i.e., PHQ-9). 


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4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
1. BMI ≥ 31 kg/m² (or 28 kg/m2 with obesity-related comorbidity)  
2. Age ≥ 18 years and ≤ 70 years  
3. Eligible female patients will be: 
• 
non-pregnant, evidenced by a negative urine pregnancy test 
• 
non-lactating 
• 
surgically sterile or postmenopausal, or they will agree to continue to use an accepted 
method of birth control during the study. Acceptable methods of birth control are: hormonal 
contraceptives; double barrier method (condom with spermicide or diaphragm with 
spermicide); intrauterine device; surgical sterility; abstinence; and/or postmenopausal status 
(defined as at least 2 years without menses). 
4. Subjects must: 
• 
have a primary care provider (PCP) who is responsible for providing routine care 
• 
understand and be willing to comply with all study-related procedures and agree to participate 
in the study by giving written informed consent 
• 
plan to remain in the Philadelphia area for the next 9 months or more 
4.2 
Exclusion Criteria 
1. Pregnant or nursing, or plans to become pregnant in the next 9 months. 
2. Uncontrolled hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 
mm Hg)  
3. Type 1 diabetes 
4. Type 2 diabetes 
5. A fasting blood glucose >126 mg/dL  (on second assessment after first elevated value, patients 
are excluded if they have both fasting blood glucose > 126 mg/dL and HbA1c ≥ 6.5)  
6. History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive 
heart failure, or heart block greater than first degree) 
7. Clinically significant hepatic or renal disease 
8. Hyperthyroidism 
9. Other thyroid disease, not controlled. 
10. History of malignancy (except for non-melanoma skin cancer) in past 5 years 
11. Narrow angle glaucoma 
12. Presence or history of marked agitation 
13. Current severe major depressive episode (BDI-II score ≥ 29), current active suicidal ideation, or 
history of suicide attempts within the past 5 years. 
14. Any severity of thought or bipolar disorder, or bulimia nervosa. 
15. Psychiatric hospitalization within the past 6 months 
16. Self-reported alcohol or substance abuse within the past 6 months, including at-risk drinking 
(current consumption of ≥ 14 alcoholic drinks per week) 
17. Past year history of drug abuse. 
18. Use in the past 2 weeks of monoamine oxidase inhibitors. 
19. Current use of serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, duloxetine, 
desvenlafaxine, milnacipran, levomilnacipran).  
20. Use in past 6 months of medications known to induce significant weight loss (i.e., prescription 
weight loss medications) or weight gain (e.g., chronic use of oral steroids, second generation 
antipsychotics) 
21. Loss of ≥ 5% of initial body weight within the past 6 months 
22. History of (or plans for) bariatric surgery (e.g., roux en y gastric bypass, sleeve gastrectomy, 
gastric banding), endoscopic intragastric balloon, or aspire assist.  


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23. Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity (e.g., 
swimming) 
24. Known or suspected allergy to sympathomimetic amines or related products 
25. The receipt of any investigational drug within 6 months prior to this trial 
26. Previous participation in this trial (e.g., randomized and failed to participate) 
27. Changes to any chronic medication (type or dosage) within the past 3 months. 
28. Any serious or unstable medical or psychological condition that, in the opinion of the investigator, 
would compromise the patient’s safety or successful participation in the study 
 
Other Therapy: Subjects will be expected to use medications (prescribed by their PCP) to control traditional 
cardiometabolic risk factors (e.g., hypertension, hypercholesterolemia, etc) and other co-morbid conditions, 
with the exception of medications listed above under “exclusions.” In all cases, the subjects’ PCP will be 
asked at the study’s outset to keep medication does constant throughout the study, whenever possible. 
Subjects will be expected to have been on their medication regimen (including the dose) for 3 months prior 
to beginning the BT program. 
4.3 
Randomization Criteria 
To be eligible to participate in the randomized phase of the trial, subjects must also:  
1. Complete at least 3 out of 4 treatment sessions during the 4-week BT run-in and attend a 
randomization visit. Attending an in-person makeup session within one week of a missed visit will 
count as having attended the run-in visit. 
2. Lose < 2.0% of initial weight during the 4-week BT run-in. 
 
Subjects who complete at least 3 out of 4 treatment sessions during the 4-week BT run-in and have lost ≥ 
2% of initial weight at the randomization visit will be provided with 24 weeks of BT during phase 2 of the 
study, but will not be eligible for randomization to a study medication. 
4.4 
Subject Recruitment  
Subjects will be recruited from the greater Philadelphia area via flyers and online, radio, and print 
advertisements, through referrals from Penn primary care practices, and through Penn’s iConnect system. 
All recruiting materials used in the study will have IRB approval. 
4.5 
Duration of Study Participation 
The total duration of the study subjects’ participation is expected to be 8 months. This includes a screening 
visit, baseline visit, 28 total weeks of BT (4 weeks before and 24 weeks after the randomization visit), and 
a post-treatment assessment.  
4.6 
Total Number of Subjects and Sites  
Recruitment will end when 150 subjects are enrolled. It is expected that approximately 50 of these subjects 
(33%) will become classified as early non-responders to BT and enrolled in the randomized trial. 
4.7 
Vulnerable Populations:  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
5 
Study Interventions  
5.1 
BT Run-in  
All subjects will complete an initial 4-week BT program in which they will attend weekly individual weight 
loss sessions of 20-30 minutes led by practitioners with training and experience in the delivery of BT (e.g., 
registered dietitians (RDs), NPs, psychologists). Subjects will be instructed to consume a self-selected diet 
of 1200-1500 kcal/day (for those who weigh < 250 lb) or 1500-1800 kcal/day (for those who weigh ³ 250 
lb) and be asked to begin to gradually increase their physical activity levels. Subjects will be counseled on 
how to consume a well-balanced diet and will be taught to use calorie counting and self-monitoring (e.g., 


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Myfitnesspal, paper diaries) to meet their goals.  
5.2 
BT Intervention 
Following randomization, all subjects will continue to attend individual (20-30 minute) BT sessions weekly 
for 12 weeks, then every other week until week 24 (total of 18 sessions). Subjects will be instructed to 
continue to follow their calorie goal and to engage in low-to-moderate intensity physical activity (e.g., 
walking), gradually building to a goal of ³180 minutes per week (spread across 5 days) by week 24. They 
will be provided a curriculum on behavioral weight control, based on prior studies, 80, 81 that includes self-
monitoring, stimulus control, goal-setting, problem-solving, cognitive restructuring, and relapse prevention. 
Subjects will continue to monitor their food intake, physical activity, and weight online (e.g., Myfitnesspal) 
unless they prefer paper diaries. Subjects who miss a treatment visit will be contacted by the research 
coordinator and invited to complete a make-up session with study staff. 
Initially, BT sessions were primarily provided in-person (make-up sessions were conducted in person 
or by phone). Consistent with University policy, all BT sessions will be provided by telehealth (phone or 
secure teleconferencing system) while recommendations to maintain remote activities due to COVID-19 
remain in place.  
BT interventionists will include RDs, NPs, and psychologists who are experienced in delivering lifestyle 
modification. Before beginning the study, interventionists will receive a 2-hour overview of obesity and its 
behavioral management, followed by ongoing weekly group clinical supervision.  The PI will observe each 
provider delivering a treatment session at least once every 6 months to provide individualized feedback and 
ensure protocol adherence. 
5.3 
Medication and Placebo Interventions 
In addition to attending BT sessions, non-responders will take a once daily study medication (phentermine 
or placebo) beginning at the randomization visit. The study medication will be provided in capsule form, and 
participants will be encouraged to take the medication in the morning upon awakening. Subjects will receive 
a 30-day supply of the study medication on each of 6 occasions. Phentermine will be provided as 8.0mg/d 
for the first 2 weeks to facilitate its acceptance to participants. The dose will be increased at week 2 to 15 
mg/d (or further placebo) in all participants. Phentermine (or placebo) will be down-titrated (back to 8.0mg/d) 
or terminated in patients who report that they cannot tolerate the medication after a prolonged effort to do 
so.  Down-titration will be managed in a blinded manner by Penn’s Investigational Drug Service (IDS), in 
response to notification from the principal investigator (or study co-investigators) of patients’ complaints of 
symptoms. (With IDS, we successfully used this titration method in prior randomized placebo-controlled 
trials of sibutramine for weight loss 82 and of the addition for 12 weeks of phentermine or placebo to 
liraglutide 3.0 mg. 83) Participants in whom phentermine (or placebo) is terminated will continue to receive 
BT for the remainder of the 24-week treatment period.   
5.4 
Preparation and Packaging of Study Medications 
Phentermine (and placebo) will be purchased and then packaged in blinded capsules by Penn’s 
Investigational Drug Service (IDS). IDS has prepared medications before for our Center in this manner, 
including the preparation of phentermine and placebo for a recent 12-week trial. 83 IDS will store all 
phentermine-placebo at the hospital, to be picked up on a weekly or every-other-week basis by study 
coordinators and distributed to study patients. 
5.5 
Medication Storage 
Drug supplies will be kept in a secured enclosure with limited access, both at the IDS where the 
medication is packaged, and at the Center for Weight and Eating Disorders (the Center), where it will be 
dispensed to subjects. The PI and research coordinator will ensure the availability of proper storage 
conditions at the Center. We will maintain adequate drug inventory and security at all times. Unused 
medication(s) will be stored separately from used trial medication(s). The PI will take appropriate 
precautions to prevent theft or diversion of the study drug. 


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5.6 
Blinding 
A master file of subject assignments will be kept by the pharmacists at IDS. Once a subject is randomized, 
the research team will receive a medication blister pack or container labeled with the subject identification 
number from IDS. The research team and the subject will be blinded and will not know the investigational 
product contained in the container. The blind may be broken in the case of an emergency. To request 
unblinding, the PI or a member of the study team who has been authorized by the PI will contact IDS to 
receive the relevant subject(s)’ information.  
5.7 
Administration and Accountability    
A record of product administration will be maintained by IDS and in the subject’s file by the study team, 
including the medication identification number, date of distribution, and date that the product was returned 
by the subject. A standard form will be utilized to document this information throughout the study period.  
5.8 
Subject Compliance Monitoring 
BT interventionists will briefly review the subject’s medication adherence at each visit, determining the 
number of days the medication was used each week and identifying reasons for missed doses. The number 
of doses of medication taken each week will be tracked. Interventionists will help subjects to problem solve 
barriers to adherence to the medication regimen and will refer subjects to the study physician or NP on an 
as needed basis. Subjects will be asked to return used medication containers, which will allow the study 
team to obtain an objective measure of the subject’s adherence to the medication regimen.  
 
 


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6 
Study Procedures 
Table 1. Proposed timeline of study visits and procedures for non-responders who lose < 2% and responders who lose ≥ 2% of initial 
weight after 4 weeks of intensive behavioral treatment (BT). 
 
 
  Screening 
Baseline and Start 
of IBT Run-in 
Non-
randomized 
IBT Run-in 
  Randomization 
Randomized Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Treatment 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Weeks in relation to 
randomization 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
20 
22 
24 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-responders who lose < 
2% at week 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  BT session 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Phentermine or placebo 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Medication distribution: 8.0 
  mg 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Medication distribution: 15.0  
  mg 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Responders who lose ≥ 2% at 
week 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  BT session 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  CMP, lipids 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test (for 
women of child-bearing 
potential) 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropeptides (GLP-1, 
insulin, PYY, leptin, ghrelin) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Acetaminophen test (blood 
draw at 30 minutes after 
standard preload) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Behavioral testing 
(progressive ratio task, 
delay discounting) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  Weekly VAS appetite rating 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
  Questionnaires 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Vital signs measurement 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Brief medical visit – non-
responders 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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7.1 
Screening Procedures 
Phone screens will be conducted by trained staff to assess preliminary eligibility. Individuals who appear to 
be eligible will be invited for an in-person screening visit that will include a behavioral evaluation conducted 
by a psychologist (including the PI). Prior to their screening visit, applicants will complete questionnaires 
that are administered as part of standard clinical practice at the Center for Weight and Eating Disorders: 
the Beck Depression Inventory-II (BDI-II) 84 to assess symptoms of depression; and the Weight and Lifestyle 
Inventory (WALI) 85 to provide information about the individual’s weight history, disordered eating behaviors, 
and other health behaviors (e.g., food intake, alcohol consumption).  
The in-person interview will be conducted by a psychologist, who will obtain informed consent and 
evaluate subjects’ behavioral eligibility (i.e., willingness and appropriateness to participate). This will 
include our assessment of the applicant’s mood (as measured by interview and the BDI-II) and suicidality 
(including history of suicidal ideation and behavior, as assessed at screening by interview and the 
Columbia-Suicide Severity Rating Scale 86). Subjects who remain interested and pass this portion of the 
assessment will provide a medical history and physical examination to determine medical eligibility. 
Persons who continue to remain eligible will proceed to have a fasting blood test to determine that final 
eligibility criteria are met.  Safety screening labs will include a comprehensive metabolic panel (CMP) and 
lipid panel, and a urine pregnancy test (for females of child-bearing age). An electrocardiogram (EKG) 
also will be performed to confirm medical eligibility prior to any participant’s enrollment in the randomized 
trial. We anticipate completing 180 in-person screenings to obtain an initial sample of 150 subjects. 
7.2 
Randomization Visit 
Following the 4-week BT run-in, subjects will attend a randomization visit (week 0, described to subjects as 
a “progress assessment visit”) at which their percent weight loss from the start of the BT program (week -
4) will be calculated. Subjects who have lost ≥2% of initial weight at this time will be categorized as early 
responders and will not be eligible for participation in the randomized trial. These subjects will be offered 
an additional 24 weeks of BT but will not receive a study medication.  
Subjects who have lost <2% of initial weight at the randomization visit will be categorized as early non-
responders. Trained research staff will review with randomization-eligible subjects information related to 
the study medication, including possible risks and benefits, and will confirm applicants’ willingness to 
participate prior to enrolling them in the randomized phase of the trial. Interested subjects will then have 
their eligibility confirmed by trained research staff, including completion of a urine pregnancy test. Non-
responders who remain eligible will be randomly assigned in double blinded fashion in a 1:1 ratio to receive 
either phentermine 15.0 mg or placebo, combined with an additional 24 weeks of BT. They will then meet 
with trained research staff who will instruct them in the use of the study medication and provide the first 
month’s supply of medication.  
All subjects will then complete an outcome assessment, as described below. 
7.3 
Outcome Assessments 
All subjects will be asked to attend 3 outcome assessments, which will occur at baseline (week -5,), 
randomization (week 0) and week 24. These assessments will include an evaluation of potential predictors 
of weight loss and assessment of the primary outcome measures used to judge the effectiveness of the 
treatments in inducing weight loss (described below). BT responders (who do not participate in the 
randomized trial) will provide weight, CVD, and questionnaire outcome measures at week 24, but will not 
be asked to complete the other portions of the in-person assessment at that time. 
Each in-person outcome assessment visit will take approximately 2 hours. Subjects will be asked to 
fast for 8 hours prior to the in-person visit (overnight fast).  Questionnaire measures will be completed online 
within 2 weeks of the in-person visit. A paper version of these measures will be provided to subjects upon 
request.  
7.4 
Treatment Visits 
As described above, subjects will attend 4 initial, once weekly, 20-30 minute, individual BT sessions (“BT 
run-in;” week -4 to week -1). The first BT session will be scheduled immediately following the baseline 
outcome assessment.  After completing the randomization visit (week 0), all subjects will continue to attend 


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BT sessions, provided in the same treatment format, weekly for the first 12 weeks (12 sessions) and every-
other-week for the last 12 weeks (6 sessions).  
7.5 
Missed Visits 
Subjects who miss a treatment visit will be contacted by the research coordinator and invited to complete 
a make-up session with study staff, in person or by phone (except for visits at which medication is 
distributed). Subjects who do not attend a randomization visit within 2 weeks of the end of the BT run-in will 
not be eligible to continue participation in the study. All subjects who complete a randomization visit will be 
invited to complete the week 24 assessment, even if they have discontinued the study medication or 
attendance of BT visits.  
7.6 
Subject Withdrawal  
A subject may voluntarily withdraw from the study at any time for any reason. The investigator or sponsor 
also may withdraw the subject from further participation at any time, if it is considered in the best interest 
of the subject or the study, without prejudice to the subject’s future medical care. It will be documented 
whether or not each subject completes the clinical study.  
The primary reason for a subject’s premature discontinuation from the study will be selected from the 
following standard categories and documented in the source documents: 
 
Adverse event (AE): One or more clinical or laboratory events which, in the medical judgment of the 
investigator, are grounds for discontinuation, even if the event does not appear to be related to study drug. 
The subject may withdraw because of an AE even if the investigator does not feel that it is grounds for 
discontinuation. This category includes subject death. 
 
Withdrawal of consent: The subject desires to withdraw from further participation in the study. 
 
Lost to follow-up: In the case of subjects who do not return to the center for study procedures and 
cannot be contacted, study personnel will make vigorous and repeated attempts (minimum of 3) to contact 
the subject. If all attempts to contact the subject fail, that subject will be considered to be lost to follow-up 
and discontinued from the study. 
 
Protocol violation: The subject’s laboratory or other findings or conduct fail to meet the protocol entry 
criteria or fail to adhere to the protocol requirements. 
 
Subject pregnancy or intention of becoming pregnant 
 
The Stopping Criteria for individual subjects include: 
 
1. The Principal Investigator and/or Medical Monitor conclude it is unsafe for the subject to 
continue. 
2. A new diagnosis is made of a significant medical condition which could influence the response 
to phentermine (e.g., congestive heart failure). 
3. A medication is begun that could alter the subject’s responses to phentermine. 
 
Subjects meeting individual stopping criteria will be withdrawn from the trial. 
7.7 
Early Termination Visits   
Whenever possible, subjects who withdraw early or who are asked by the investigator to cease participation 
in the study will have one final visit to collect study medication and to follow up regarding adverse events. 
8 
Study Evaluations and Measurements  
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8.1 
Primary Outcome Measure: Body Weight 
Body weight will be measured at screening and at all clinic visits. However, for purposes of the primary 
outcome, weight will be assessed during outcome assessments at baseline (at the start of the BT run-in); 
at randomization (week 0); and at week 24. Weight will be measured on a digital scale (to the nearest 0.1 
kg) with subjects dressed in light clothing, without shoes. Two measurements will be taken on each 
occasion.  
8.2 
Phase 1 Predictor Variables  
8.2.1 
Appetite, Neuropeptides, and Gastric Emptying 
During the two-hour in-person outcome assessment at baseline (week -5), randomization (week 0) and 
week 24, subjects will first complete measures of appetite, neuropeptides, and gastric emptying before and 
for 60 minutes after consumption of a liquid test meal (e.g., Muscle Milk). The test meal size (oz and kcal 
will vary by sex with women consuming 70% of the amount provided to men. Subjects will be asked to fast 
for 8 hours prior to the in-person assessment (overnight fast), and research staff will confirm the timing of 
the subject’s last ingestion prior to beginning the assessment. 
Appetite measures are perceived ratings of hunger, fullness, and satiety that reflect both objective 
(e.g., physiological) and subjective (e.g., learned) components of appetite. They will be assessed using 
100-mm visual analog scales (VAS) with opposing anchors (e.g., “extremely full” to “not at all full”). 16, 17 
The satiety quotient (SQ) will be the primary measure of perceived satiety and reflects the extent to which 
the liquid test meal reduces appetite sensations per unit of intake (e.g., kcal), 16, 17 calculated as: SQ 
(mm/kcal) = [(fasting rating before preload – 60 min post-preload rating)] / (energy content of preload) x 
100. Physiological appetitive response will be measured as: 1) fasting levels of circulating neuropeptides 
associated with appetite (GLP-1, insulin, PYY, leptin, and ghrelin); 2) postprandial changes in these 
neuropeptides, calculated as the 60-minute area under the curve (AUC); 45 and 3) gastric emptying as 
assessed by an acetaminophen test (60-minute AUC).87-89 Because acetaminophen is minimally absorbed 
by the stomach but quickly enters the bloodstream in the small intestine, gastric emptying is considered to 
be the primary factor influencing its appearance in the blood. 87-89 Maximum blood concentration of 
acetaminophen is reached in 30 to 60 minutes; therefore, the 60-minute AUC is thought to represent rapidity 
of gastric emptying.89 
Blood samples and VAS scales will first be completed in a fasted state. Subjects will be given 1.5g of 
acetaminophen with 50 ml of water. 87-89  They will then be asked to consume a liquid test meal within a 10-
minute period. Subjects will repeat VAS ratings at 10-minute intervals after consumption of the test meal.27 
Postprandial blood samples will be collected at 30- and 60-minutes post-ingestion to evaluate changes in 
circulating neuropeptides and acetaminophen absorption. Protease inhibitors and DPP4 inhibitors will be 
added to samples to be assayed for GLP-1, PYY, and ghrelin to prevent enzymatic breakdown. Samples 
will be centrifuged at 4°C, separated, and frozen at −80°C for later analysis.  
8.2.2 
Impulsivity 
After completion of the final blood draw and appetite ratings, subjects will complete measures of impulsivity 
(delay discounting; DD), reinforcing efficacy (questionnaire), and the relative reinforcing value of food 
(RRVfood; baseline [week -5] only). The completion of these tasks following consumption of the liquid meal 
is designed to reduce the effect of hunger on food reinforcement. e.g., 33 
DD is conceptualized as an aspect of impulsivity that reflects difficulty with inhibiting responses to 
rewarding stimuli. The measure indicates the degree to which delaying an outcome reduces its perceived 
value. DD will be assessed via a computer program in which subjects are offered choices between small, 
immediate rewards and larger, delayed rewards. e.g., 28, 32 The size of the larger amount is fixed, while the 
size of the smaller reward and length of delay vary between trials. Indifference points are calculated as the 
point at which the subject switches preference from the immediate to the delayed reward, and the AUC 
(representing the ratio of immediate reward size to time delay) will be used as the primary outcome.28, 32   
8.2.3 
Relative Reinforcing Value of Food 
RRVfood refers to how hard a person is willing to work to gain access to a food reinforcer. Subjects are 
allowed to work to earn points from a slot machine task at either of two computer stations, one of which 


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provides points towards obtaining a preferred high-calorie food, and the other points towards a preferred 
low-calorie food. e.g., 29, 30  Points are earned on a progressive ratio scale that increases at fixed intervals. 
The primary outcome is the number of food reinforcer points earned, which is thought to reflect the subject’s 
willingness to allocate time and effort to obtaining desired foods.  
8.3 
Cardiometabolic Risk  
To evaluate exploratory outcomes, cardiometabolic risk factors will be assessed at screening, 
randomization (week 0) and week 24.  Fasting blood samples (i.e., following an overnight fast of at least 8 
hours) will be drawn on each occasion and assayed for a CMP and lipid panel. (Samples will be analyzed 
by Quest Diagnostics.) Responders who are not randomized will not complete the CMP and lipid panel at 
randomization (week 0). All participants will complete these analyses at screening and at week 24.     
Blood pressure and pulse will be measured on each occasion using an automated monitor (Dinamap, 
model 9300). Two readings will be taken on each occasion (at 1-minute intervals), after subjects have been 
seated for at least 5 minutes. Waist circumference (measured horizontally halfway between the lowest rib 
and the top of the hipbone) to the nearest 0.1 cm will be assessed on the same schedule. Two waist 
measurements will be obtained at each assessment visit. 
8.4 
Questionnaire Measures 
Eating characteristics. Self-report measures of hunger, impulsivity, and the relative reinforcing 
value of food will be administered to all subjects at all three outcome assessments. The Eating Inventory 
(EI – hunger subscale 90) and one-week VAS ratings will be used to assess hunger. RRVfood will be 
assessed by the Power of Food Scale (PFS 91) and general sensitivity to reward will be assessed by the 
Behavioral Inhibition/Activation Scale (BIS/BAS).92 The Barratt Impulsiveness Scale (BIS-15)93 will be used 
to assess impulsivity. We will also collect measures of additional eating characteristics for use in exploratory 
analyses, including past-week VAS appetite ratings 94, cognitive restraint (EI), disinhibition (EI), and binge 
eating (Questionnaire on Eating and Weight Patterns [QEWP-5]95). Craving frequency will be assessed 
using the Food Craving Questionnaire – Trait – reduced (FCQ-Tr)96 and emotional eating using the Dutch 
Eating Behavior Questionnaire (DEBQ)97 Emotional Eating subscale. Perceived barriers to health behavior 
change 98, diet and exercise self-efficacy (i.e., Weight Efficacy Life-Style Questionnaire [WEL]99, SCI 
Exercise Self Efficacy Scale [ESES]100), social support for healthy eating and physical activity (i.e., Ball and 
Crawford Social Support Scale)101, will also be assessed. Reinforcing efficacy of high- and low-energy 
density snack foods and active and non-active activities will be assessed using a computerized 
questionnaire during the in-person assessment.114 Food addiction will be assessed using the Yale Food 
Addiction Scale (YFAS).115 
The Highly Processed Food Withdrawal Scale (ProWS)116 will be administered on a separate 
timeline from the questionnaires described above. Participants will first complete the ProWS at their 
screening visit (week -5) and will be sent an email every other day with a link to complete this questionnaire 
until the second intervention visit (week -2). This timeline will allow us to assess indicators of withdrawal 
that may develop early in treatment when an individual attempts to cut down on highly processed foods.  
Psychosocial characteristics. Psychosocial characteristics will be assessed on the same 
schedule as the primary outcomes. Mood will be assessed using the PHQ-9102 and the C-SSRS86. 
Perceived stress will be assessed using the Perceived Stress Scale (PSS)103 and anxiety using the GAD-
7. Quality of life will be assessed using SF-36.104 The Philadelphia Mindfulness Scale (PHLMS) will be used 
to assess general mindfulness and acceptance.117 Physical activity will be assessed by the Paffenbarger 
Physical Activity Survey.105 A brief questionnaire will assess hours of sleep per week.118 
9 
Statistical Plan 
9.1 
Sample Size and Power Determination 
A total sample size of 150 subjects will provide at least 80% power to detect all three primary outcomes. All 
power analyses were conducted using G*Power 3.1 at an alpha of .05. A correction for multiple 
comparisons is not proposed due to the preliminary nature of this research. 
Phase 1: For the co-primary outcome - percent weight loss at the end of the BT run-in as predicted by 
baseline satiety, postprandial GLP-1, and gastric emptying - an estimated effect size for each predictor of 


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f2 = .042 was selected as the lower estimate from studies predicting weight loss from VAS satiety ratings 
and GLP-1 (r’s ≥ .20). ).16, 106 (We did not find studies using gastric emptying to predict weight loss, and the 
effect sizes for comparisons between BMI categories of f2 = .07 - .30 were less conservative.43, 78) Based 
on this estimate, a sample size of 150 subjects would yield 80% power to detect statistical significance for 
the three individual predictor variables. The second co-primary outcome - non-responder status as 
predicted by these three predictors in discriminant analysis - would have 90.1% power with this sample 
size, based on power analysis for a 2-group MANOVA for 3 response variables107, 108 with an estimated 
combined effect size of f2 = .10.  
Phase 2: For the primary outcome - percent weight change from randomization to week 24 among 
early non-responders - estimated group means, variances, and attrition rates were derived from data from 
prior studies conducted at our Center and from previous research in early non-response to BT e.g., 4. The 
estimated treatment effect is based on the placebo-subtracted effect of 28 weeks of phentermine 15.0 mg 
of 4.5 kg (4.4% of initial weight), as determined by a multi-arm RCT that enrolled 219 total patients in the 
placebo and phentermine 15.0 mg groups. 77 We selected this result as the basis of our power analysis 
because it most closely matched the phentermine dose and duration used in the present study. Other 
previous RCTs examining the effect of phentermine monotherapy have typically administered a 30.0 mg 
dose for 12 to 16 weeks. The majority of these trials have achieved larger placebo-subtracted weight losses 
of 5.4 to 7.8 kg. 72, 74-76 (One randomized trial reported a 4.0 kg placebo-subtracted loss with a different 
formulation, phentermine resin 30.0 mg, 73 and one reported a 3.3% placebo-subtracted loss when both 
phentermine 37.5 mg and placebo were combined with a 900-1100 kcal/day meal replacement diet, 
resulting in large mean weight losses in both groups. 109) An additional study suggested that the difference 
in mean weight loss between phentermine 15.0 mg and phentermine 30.0 mg (both when combined with 
lorcaserin) is small (0.6 kg mean difference). 110 We therefore believe that participants provided with 24 
weeks of phentermine 15.0 mg are likely to achieve a placebo subtracted loss of ≥4.5% of initial weight. 
(Most early phentermine studies reported results in kg, which is roughly equivalent to percent weight loss 
in populations with obesity.) 
We predict a 24-week post-randomization weight loss among early non-responders of 6.5% in BT+M 
and 2.0% in BT+P, with expected standard deviations of 5.5%. We expect 33% of the initial baseline sample 
of 150 subjects to be categorized as early non-responders following the BT run-in.4, 7, 8 Based on these 
estimates, a randomized sample size of 50 non-responders (25 per group), assuming a 20% attrition rate, 
will give us 81.5% power to detect between-treatment group differences at week 24 of 4.5% (effect size: d 
= 0.82).   
9.2 
Statistical Methods 
Data quality and integrity will be checked by assessing the data for missing and out-of-range values and 
univariate normality with basic statistical procedures, including descriptive statistics and visual graphical 
displays (e.g., histograms, scatter plots). All questions of data quality and integrity will be investigated 
before any statistical modeling is conducted. To test the adequacy of randomization, preliminary analyses 
will include a comparison of demographic and baseline characteristics between randomized treatment 
groups (BT+P and BT+M; t-tests or Wilcoxon rank sum tests for continuous variables and Chi-Square test 
or Fisher’s Exact test for categorical data). If baseline imbalances are observed, the relevant variables will 
be included as covariates in analyses relevant to those outcomes.  
All analyses will be conducted using the ITT principle. Analyses will be two-tailed with an alpha of 0.05, 
and will be conducted using SPSS version 24.0 or SAS version 9.4. For all analyses, residual analyses will 
be conducted to check for outliers, influential points, and violations in the normality assumption. If violations 
are detected, variance-stabilizing transformations will be considered.  
Phase 1:  Analyses will be based on the initial population of subjects who attend at least one post-
baseline treatment visit during the BT run-in. Multiple regression will be used to evaluate predictors of early 
weight loss with BT (% loss at week 0) and discriminant analysis will be used to assess which variables 
predict categorization as a non-responder (who has lost < 2% of initial weight at week 0). The primary 
analyses will test the hypothesis that the set of baseline satiety measures (VAS satiety ratings, postprandial 
changes in GLP-1, and gastric emptying) predict these outcomes when considered simultaneously. 
Additional analyses will evaluate demographic characteristics, secondary predictor variables (fasting 
hunger, RRVfood, reinforcing efficacy of food, impulsivity, fasting ghrelin, fasting leptin, and lower 
postprandial changes in insulin and PYY), and exploratory variables as predictors of early weight loss. 


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Factor analysis will be used to assess whether predictor variables cluster into phenotypes.  
Phase 2: Primary analyses will be based on the all-randomized population. The null hypothesis being 
tested is that there will be no significant difference between non-responders assigned to BT+M and BT+P 
in mean percentage of initial weight lost at 24 weeks post-randomization. To assess the primary phase 2 
outcome of percent weight change by treatment group (among non-responders), a mixed effects model will 
be fit with treatment group (BT+P, BT+M) as a between-subjects factor and time (week) as a within-subjects 
factor. We will use the group x time interaction to estimate and test treatment group differences at week 24 
(primary endpoint). In fitting the mixed effects model with residual maximum likelihood, a variance-
covariance structure will be selected based on criteria such as the Akaike’s Information Criterion (AIC). The 
results from the mixed model will be summarized by mean (SE) for each treatment group at week 24. 
Secondary analyses comparing IBT+M and IBT+P in changes in hunger, satiety, reinforcing efficacy of 
food, and impulsivity from randomization to week 24 will be conducted using similar analytic strategies, as 
will exploratory analyses of change in cardiometabolic risk factors, quality of life, and depression. Similar 
mixed effects models also will be used to compare differences in percent weight loss from randomization 
to week 24 between early non-responders treated with BT+M and early responders who attend a 
randomization visit and are treated with BT alone. Logistic regression will be used to examine differences 
between BT+M and BT+P in percent of subjects who achieve a post-randomization loss of ³ 5% and ³ 10% 
of initial body weight at week 24. Subjects who do not provide a week 24 weight will be considered as not 
having achieved the categorical weight loss.    
  
9.2.1 
Missing Data.  
All analyses will be conducted using the ITT principle, in which all available data on all randomized patients 
are included.  This approach minimizes bias if subjects drop out of the intervention for different reasons. 
Assuming adequate fit of the mixed effects models to the data, the proposed nested random effects models 
are the most robust to missing data assumptions among standard longitudinal models that analyze all 
subjects regardless of how many post-randomization visits are missed.111 The following missing or 
unbalanced data scenarios can be accommodated by such models: attrition (drop out), missed interim 
visits, and missing covariate data where a subject is interviewed but data are missing on covariates of 
interest.  All three types of missing data are handled by way of maximum likelihood under the proposed 
mixed effects models and the missing at random assumption (MAR). Therefore, we will explore the potential 
bias of missing data by comparing completers and non-completers to see if they differ systematically on 
values of non-missing variables. There are many ways to assess the assumption of MAR. We will consider 
imputing missing endpoint data using multiple imputation techniques, fitting selection models (e.g. MNAR), 
and fitting pattern mixture models. Sensitivity analyses, including an analysis of the protocol-compliant 
population, also will be conducted. 
 
Participants’ data will be excluded from analyses in the event of pregnancy, amputation, bariatric surgery, 
or death. Any data collected following such events will be treated as missing, using the analytic methods 
described above. Additional criteria associated with subject censorship will be considered prior to initiating 
recruitment.   
9.3 
Subject Population(s) for Analysis 
• Initial population: Any subjects who complete a baseline assessment and attend at least one post-
baseline treatment session during the BT run-in 
• All-randomized population:  Any subjects who lose < 2% of initial weight during the BT run-in, attend 
a randomization visit, and are randomized to participate in the 24-week RCT comparing BT+M to 
BT+P 
• Protocol-compliant population:  Any subject who was randomized and received the protocol required 
investigational product exposure and required protocol processing during the RCT 


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10 Safety and Adverse Events 
10.1 Definitions 
10.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study, whether or not considered drug related.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
10.1.2 Serious Adverse Event  
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event  
 
The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of death 
at the time of the event. It does not refer to an event which hypothetically might have caused death if it was 
more severe. 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
10.2 Recording of Adverse Events 
All events meeting the definition of an adverse event will be collected and reported from the first trial related 
activity after the subject has signed the informed consent and until the end of the 24 week treatment period 
as stated in the protocol. At each contact with subjects, study personnel will be responsive to reports of 
AEs with specific questioning and, where appropriate, by physical examination. Information on all adverse 
events will be recorded immediately in the source document and reported immediately, and also in the 
appropriate adverse event module of the case report form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results will be recorded in the source document, though should be grouped 
under one diagnosis. 
 
All AEs occurring during the study period will be recorded. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome. Any SAE that occurs after the study period and is 
considered to be possibly related to the study intervention or study participation will be recorded and 
reported immediately. 


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The study PI is ultimately responsible for the recording, and reporting, unanticipated problems related to 
the research, which occur during the study.  
10.3 Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be characterized by the PI in 
consultation with the study physician. The relationship of AEs to the study will be classified as follows: 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
• Possible: A causal relationship is conceivable and cannot be dismissed 
• Unlikely: The event is most likely related to an etiology other than the trial product 
10.4 Reporting of Adverse Events and Unanticipated Problems 
The PI will report all adverse events including serious adverse events (SAEs, as defined above) to the 
Safety Monitoring Committee established for the trial, and to the Penn IRB. All serious adverse events will 
be reported to the IRB within 72 hours, as required.  
 
If the SAE report is supplied as a narrative, the minimum necessary information to be provided at the time 
of the initial report will include: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study intervention 
 
Additionally, all other events (unanticipated problems, adverse reactions, and subject complaints) will be 
recorded and reported with respect to institutional and federal policies as described in the Penn Manual.  
 
10.4.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) will be submitted to the IRB. The PI is 
responsible for ensuring that all SAE are followed until either resolved or stable.  
 
10.4.2 Pregnancy 
Study subjects will be instructed to notify the investigator immediately if they become pregnant. Reporting 
of pregnancy by the investigator will occur within the same timelines described above for reporting of 
Adverse Events. Pregnancy complications will be recorded as adverse event(s). If the infant has a 
congenital anomaly/birth defect this will be reported and followed up as a serious adverse event.  
 
There is no documented risk for males who reproduce while taking phentermine. Reported pregnancy in a 
non-participating female partner of a study subject will not be considered an adverse event, and follow-up 
data will not be requested.  
 
Randomized female participants who have received a study medication and have become pregnant during 
the trial period will be followed until the pregnancy outcome and the new-born infant is 1 month of age. 
“Pregnancy outcome” is defined as the end of pregnancy: live birth, fetal death, or termination of pregnancy.  
Data will be collected via the participant’s self-report; we will also attempt to obtain medical records related 
to the pregnancy and the pregnancy outcome.  
 
The following information will be collected from all participants at the time of the reported pregnancy:   
 
• 
Date of investigator’s first knowledge of the pregnancy 
• 
Participant weight and height at the time of becoming pregnant 


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• 
Whether the participant was exposed to a study medication, including medication start date, stop 
date, and dose at the time of withdrawal from the study 
• 
First day of last menstrual period 
• 
Expected date of delivery (if known) 
• 
Number of fetuses (if known) 
• 
Relevant risk factors and diagnoses with an onset prior to the current pregnancy (e.g., parvovirus; 
inheritable disease; rubella; toxoplasmosis; type 1 or 2 diabetes mellitus; gestational diabetes 
mellitus; cytomegalovirus; heart disease; hypertension; congenital anomaly [in mother]; 
psychomotor retardation; psychiatric illness during pregnancy; chemotherapy; radiation therapy; 
teratogenic exposure; thyroid disease; seizure disease; hepatitis A, B, C, or D; rhesus [RH] 
negative; tobacco, alcohol, or substance use during pregnancy; consanguinity; other past/current 
diagnoses or factors which could affect pregnancy outcome) 
• 
Relevant risk factors and diagnoses with an onset during the current pregnancy 
• 
Any adverse events experienced in connection with the current pregnancy 
• 
Any adverse events occurring in the fetus during the current pregnancy  
 
The following information will be collected from all randomized participants after the pregnancy outcome:  
 
• 
Date of pregnancy outcome 
• 
Gestational age at time of pregnancy outcome 
• 
Whether the pregnancy resulted in a live birth.  
o 
If yes: number of live births and whether infant(s) was/were diagnosed with congenital 
anomalies at birth. 
• 
Whether the pregnancy resulted in fetal death. 
o 
If yes: number of fetal deaths, early (before 20 weeks gestation) or late (after 20 weeks 
gestation), and whether the fetal death(s) were due to congenital anomalies 
• 
Whether the pregnancy was terminated 
o 
If yes: whether the pregnancy was terminated due to congenital anomalies 
• 
Delivery information (if applicable): vaginal or cesarean section, whether complications occurred 
during delivery 
• 
For each live birth:  
o 
Gender 
o 
Length and weight at delivery 
o 
Apgar score at 1, 5, and 10 minutes (if known) 
o 
Diagnosis of health problems at delivery 
o 
Diagnosis of health problems between birth and age 1 month 
o 
Was the newborn diagnosed with congenital anomalies 
10.5 Unblinding Procedures 
Breaking of the blinding code will occur at the request of the PI following completion of the week 24 
assessment of the last enrolled subject.   
The code for a particular subject may be broken in a medical emergency if knowing the identity of the 
treatment allocation would influence the treatment of the subject or if demanded by the subject. Whenever 
a code is broken, the person breaking the code must record the time, date and reason as well as his/her 
initials in the source documents. All codes (whether broken or not) will be kept throughout the trial period.  
Accountability of all broken or unbroken codes (hard copy or electronic) will be performed at or after trial 
closure. 
10.6 Medical Monitoring 
Safety endpoints include physical examination, adverse events (AEs), and standard laboratory tests. In 
addition to assessment visits, randomized subjects will have a brief medical monitoring visit (10-15 minutes) 
with study staff (e.g., registered nurse) at week 2 (after 2 weeks at the 8.0 mg dose) and week 4 (after most 
subjects will have completed 2 weeks at the 15.0 mg dose) to monitor response to the medication. Study 


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subjects will be asked whether there has been any change in their health or medications. The study NP or 
physician will be available to assess the subject and evaluate and treat any adverse events. 
Side effects will be queried during every study visit, and the study NP or physician will be available to 
assess the subject and evaluate and treat any adverse events. Subjects will be encouraged to contact study 
staff immediately should an AE occur between visits, and 24-hour contact information will be provided for 
study personnel and the study physician. If any AE requires treatment follow-up, subjects will be provided 
with appropriate referrals. 
Subjects will have fasting blood draws (CMP and lipids) at screening, and at randomization (week 0; 
randomized subjects only) and week 24. Vital signs (blood pressure and pulse) will be measured at 
screening and any in-person visits occurring in weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24.  
10.6.1 Data and Safety Monitoring Plan 
Purpose.  The data and safety monitoring plan is included to ensure the safety of subjects and verify the 
integrity of the data. This monitoring plan outlines the procedures for data verification and integrity, safety 
parameters, and monitoring and completion of regulatory documents.  
Risk of Study.  This study is anticipated to pose minimal risk. Intensive BT poses minimal risks and 
improves weight and health outcomes for the average subject. Phentermine 15.0 is an FDA-approved 
medication that has proven to be safe in persons with obesity and obesity-related comorbidities. 
Phentermine was approved by the Food and Drug Administration (FDA) in 1959 for “short-term” use, 
commonly interpreted as 12 or fewer weeks. The FDA had not yet begun to require long-term trials for 
obesity drugs at that time. 69 In 2012, the FDA approved the combination of phentermine (7.5 – 15.0 mg/d) 
plus topiramate for long-term weight management (e.g. ≥12 months). Phentermine (monotherapy) is the 
most widely used weight loss medication in the U.S. and is frequently prescribed in clinical practice for 
periods longer than 12 weeks. 69-71 A recent study of a large cohort of 13,972 individuals who had received 
phentermine found that risk of the composite outcome of a cardiovascular event or death was rare (0.3%) 
and that there was no increase in risk associated with a longer duration of phentermine use (up to 2 years). 
69 The FDA did not require an Investigational New Drug (IND) application for the use of phentermine in the 
present study.  
Who Will be Responsible for Monitoring?  The PI (Dr. Tronieri) will be responsible for overseeing 
and monitoring the study. Safety and data quality monitoring will be performed on an ongoing basis by the 
PI and research coordinator, in consultation with Drs. Wadden and Berkowitz (study physician).  
A Safety Monitoring Committee consisting of a safety officer and data officer will provide additional 
study oversight. This team will include at least one external (non-Center) reviewer. The Committee will be 
responsible for executing the data safety and monitoring plan, monitoring trial safety and efficacy, and 
complying with Public Health Service reporting requirements. This team will meet prior to the start of 
recruitment to review the protocol, human subjects’ protections, and plans for data and safety monitoring. 
They will then meet at least twice per year to review the study’s progress and de-identified group-level data 
for differential rates in adverse events (AEs) and key outcomes. The Committee will review adherence to 
the proposed rate of subject enrollment, inclusion/exclusion criteria, and diversity goals as outlined in this 
protocol. 
How Will Monitoring be Performed?  Safety and data quality monitoring will be performed on an 
ongoing basis by the PI and research coordinator, in consultation with co-investigators (including the study 
physician). The research coordinator will oversee the collection and entry of all study data. This includes 
ensuring that source documents exist for the data, that fields are completed appropriately, and that 
corrections are entered according to Good Clinical Practice guidelines. Any deviations from study 
procedures will be documented and reported to the Safety Monitoring Committee and the IRB.  
Prior to conducing final data analyses, data will be checked for systematic errors and missing data, 
and a random subset of primary and secondary outcome data that has been entered manually will be 
checked against source documents to identify errors.  
Study Initiation.  The PI will be responsible for assuring that all staff and subjects understand and 
accept the obligations incurred in undertaking this study in accordance with all applicable regulations; the 
obligation to obtain informed consent; the obligation to obtain IRB review and approval of a clinical 
investigation before the investigation may be initiated and to ensure continuing review of the study by the 
IRB; and to keep the sponsor informed of such IRB approval and subsequent IRB actions concerning the 
study.  


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Ongoing Monitoring Meeting.  Monitoring will be conducted in accordance with the Penn’s Sponsor-
Investigator Standard Operating Procedure. Monitoring meetings will be held regularly throughout the 
study. The first meeting will occur no later than two weeks after the first subject is enrolled. Subsequent 
monitoring will occur at weekly study meetings of research staff at the Center, including the PI and the study 
physician. At these meetings, the team will review subject accrual and retention, protocol compliance, 
reported side effects and AEs, and any other subject issues. The PI will meet semi-annually with the Safety 
Monitoring Committee.  
Assessing Adverse Events.  Monitoring for AEs will be conducted in real-time by all study personnel 
who have direct contact with subjects. Side effects will be queried during each study visit, and the study NP 
or physician will be available to assess the subject and evaluate (e.g., time of onset, nature of issue 
reported) and treat any potential AEs. Subjects will be instructed to contact study staff, including the study 
physician, if they experience any AE between study visits. The study physician or NP will determine the 
severity of the AE, its possible relation to phentermine treatment using standard criteria (not, possibly, 
probably, or definitely related), and the appropriate course of action for the study subject.  
Reporting of Adverse Events.  The PI will review all of the Adverse and Unexpected Event Case 
Report Forms, in collaboration with Drs. Wadden and Berkowitz. After removal of identifying patient 
information, all AEs will be reported to Penn’s IRB and the Safety Monitoring Committee. Serious Adverse 
Events (SAEs) will be brought to the attention of the PI and study physician within 24 hours and to the 
attention of the IRB within 72 hours, as required. All adverse events and unanticipated problems (UPs) will 
be recorded, and a summary table will be presented to the IRB and DSMB annually.  
Data, Safety and Monitoring Report. The PI will provide a summary of the data, safety, and 
monitoring report to the IRB and Safety Monitoring Committee on an annual basis. The report will include 
the subjects demographic characteristics, expected versus actual accrual rates, retention rates, any quality 
assurance or regulatory issues that occurred since the previous report, summaries of AEs, SAEs and UPs, 
and any actions or changes with respect to the protocol.  
Evidence of Training in Human Subjects Research.  All research personnel associated with this 
study will have completed Penn’s CITI training for patient oriented research and HIPAA compliance training. 
Documentation of this training will be maintained in the study regulatory binder. The PI will directly supervise 
all members of the research team.  
11 Study Administration, Data Handling and Record Keeping 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
11.2 Data Collection and Management  
The following data will be collected from subjects for research purposes:  1) questionnaires assessing 
demographic characteristics, weight loss history, health behaviors (e.g., eating habits and physical activity), 
quality of life, depression, hunger, satiety, the relative reinforcing value of food, and impulsivity; 2) medical 
history to evaluate exclusion criteria and cardiometabolic risk; 3) measurements of weight, height, waist 
circumference, and blood pressure; 4) blood samples sent to Quest Diagnostics to assess cardiometabolic 
risk factors; 5) blood samples sent to the Hayes laboratory or Translational Core laboratory at Penn to 
assess concentration of circulating neuropeptides; 6) urine samples for pregnancy testing; and 7) in-person 


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assessment of appetite before and after a liquid test-meal and behavioral assessments of delay discounting 
and the relative reinforcing value of food, collected via computer. Computer-based assessments of delay 
discounting and the relative reinforcing value of food will be collected in EPrime. Questionnaire data will be 
entered directly in RedCap by subjects (except for those requesting paper forms). Trained study personnel 
will enter other data from source documents into RedCap and a random subset of the primary and 
secondary outcome data that has been entered manually will be checked against source documents to 
identify errors.  
All research personnel will complete Penn’s Collaborative Institutional Training Initiative (CITI) 
Protection of Human Subjects Research Training and HIPAA Compliance Training. Study staff involved in 
handling biological samples will complete additional IRB training in bloodborne pathogens. Subjects will be 
assigned an ID that will be used in all study communications. Research datasets will include only subject 
IDs, with a separate, password-protected dataset linking names and ID numbers. Study information will be 
stored electronically in a password-protected drive or kept in locked files. 
All applicable national and international guidelines, regulations, and Institutional Review Board (IRB) 
guidelines regarding subject privacy and confidentiality will be followed throughout the study. No identifying 
information will be included with stored research data, biological samples, clinical data, or reports of results. 
Penn network firewalls prevent unauthorized internal access to data, external access to data, and malicious 
intent to destroy data and systems. Controlled user access will ensure that only appropriate and authorized 
personnel are able to view, access, and modify study data. Data sent to the IRB, Investigational Drug 
Services, or the Safety Monitoring Committee will contain no identifying information, except as required 
when reporting AEs. Password-protected files linking subject names and ID numbers will only be accessible 
to the PI and research coordinator, and will be stored in a locked office.  
11.3 Records Retention  
We will retain all Essential Documents in accordance with Federal regulation and International 
Conference on Harmonization (ICH) Good Clinical Practice (E-6) and 45 Code of Regulations (CFR) 
part74.53, which requires awardees to retain records pertinent to an award for a period of three years 
from the date of submission of the final expenditure report.  
12 Study Monitoring, Auditing, and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
13 Ethical Considerations 
This protocol and any amendments will be submitted to the Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.  The decision of the IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided 
to the sponsor before commencement of this study. The principal investigator (PI) will initiate and enroll 
subjects only after receiving IRB approval of the protocol and the informed consent documents. All recruiting 
materials used in the study will have IRB approval. Progress reports regarding the study will be submitted 
to the IRB in accordance with institutional and regulatory guidelines.  
The study will be performed in compliance with applicable US government regulations and with the 
FDA Code of Federal Regulations for Good Clinical Practice (GCP). These procedures ensure the 
protection of the rights and the integrity of the subjects, adequate and correct conduct of all study 
procedures, adequate data collection, adequate documentation, and adequate data verification.  
Before being enrolled, subjects will be provided informed consent. The nature, scope, and possible 
consequences of the study will have been explained in a form understandable to them. A copy of the 
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Subject confidentiality will be maintained throughout the study according to applicable guidelines, 
regulations and IRB requirements. All laboratory samples, study clinical data, and reports of results will de-
identify individual subjects. Subjects will be identified by initials, date of birth, and subject number only for 
use in data collection. Published data will provide subject numbers only if needed for clarity of presentation 
(e.g., in individual event listings).  
The study will be conducted in accordance with the Declaration of Helsinki. The study will be conducted 
in accordance with the ICH GCP guidelines. The sponsor-investigator will comply with all applicable 
regulatory and legal requirements, ICH GCP guidelines, and the Declaration of Helsinki in obtaining and 
documenting the informed consent. 
13.1 Risks 
Potential Risks of Weight Loss Intervention: Rapid weight loss (loss of > 3 lb. per week for 3 or more 
weeks) may increase the risk of gallstones. Symptoms of gallstones include abdominal pain, nausea, 
vomiting, fever, and chills. Rate of weight loss will be monitored in all subjects to identify those at risk. 
 
Potential Risks of the Medication: The following are the common side effects that have been reported 
with phentermine treatment (because the medication was approved in 1959, they do not have a defined 
frequency): high blood pressure, palpitations, elevated heart rate (tachycardia), dizziness, overstimulation, 
restlessness, insomnia, changes in mood (euphoria or dysphoria), changes in libido, tremor, headache, dry 
mouth, unpleasant taste, diarrhea, constipation, and other gastrointestinal disturbances.  
Rare side effects that may be associated with taking phentermine include:  
 
• 
Acquired Valvular Heart Disease. Cases of developing heart valve disease were reported in 
people taking phentermine in combination with fenfluramine. Fenfluramine appeared to be 
responsible for the valvular heart disease. It was removed from the market in 1997. Phentermine 
did not appear to contribute to valvular heart disease, but this possibility cannot be completely ruled 
out.   
 
• 
Primary Pulmonary Hypertension. This condition is a rare, frequently deadly disease of the 
lungs. It was observed in persons who took the combination of phentermine and 
fenfluramine.  Fenfluramine appeared to be responsible for this illness and was removed from the 
market.  The possibility of an association between primary pulmonary hypertension and the use of 
phentermine alone cannot be ruled out. No cases of the disease have been reported with the long-
term use of phentermine and topiramate, marketed as Qsymia.   
 
• 
Abuse Potential. Phentermine is chemically and pharmacologically similar to amphetamines 
which have a high abuse potential. One study found no signs of drug craving, abuse, dependence, 
or amphetamine-like withdrawal upon abruptly ceasing the medication, even at doses higher than 
typically recommended and after treatment durations of up to 21 years. 71 However, the possibility 
of abuse with phentermine should be considered in deciding whether to prescribe this medication. 
Individuals who have a history of drug abuse will not be eligible to participate. 
 
• 
Central Nervous System Effects.  Phentermine may impair physical and mental abilities. Caution 
should be taken when driving or operating machinery, or drinking alcohol. Individuals with an 
overactive thyroid (hyperthyroidism) will not be eligible for to take phentermine.  
 
• 
Glaucoma. Phentermine may cause excessive dilation of the pupils which can worsen narrow 
angle glaucoma. Patients with a narrow angle glaucoma diagnosis will not be eligible to participate.  
 
• 
Drug Interactions. Use of phentermine is contraindicated during or within 14 days following the 
administration of monoamine oxidase inhibitors (MAOIs) because of the risk of hypertensive crisis. 
The effect of co-administering phentermine with selective serotonin norepinephrine reuptake 
inhibitors (SNRIs) has not been investigated. Participants will be asked to inform the study 
physician or nurse practitioner immediately if they are prescribed one of these medications during 
the study period. 


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• 
Kidney Impairment. Phentermine has not been studied in persons with kidney impairment. 
Persons with clinically significant kidney disease are not eligible for this study.  
 
• 
High Blood Pressure. Phentermine may cause an increase in blood pressure. Individuals with a 
blood pressure is ≥140/90 not be eligible to participate in this study. Individuals with a history of 
coronary heart disease, congestive heart failure, or other significant cardiovascular disease (see 
exclusions) also will not be eligible. We will monitor participants’ blood pressure at every study visit.  
 
• 
Unforeseen risks. Such risks include allergic reactions to medications. In addition, there may be 
other risks associated with phentermine that have not been identified. If additional risks are 
identified during the study, study subjects will be informed about these risks by the study team.   
 
• 
Reproductive risks. The use of phentermine may pose risks to pregnancy and/or an unborn baby. 
Therefore, subjects are advised not to get pregnant while in the study. Women of child bearing 
potential will be required to follow a study-approved method of birth control while participating in 
the study. Adequate birth control in this study is the use of double barrier methods (condom with 
spermicide or diaphragm with spermicide), stable hormonal contraception, intrauterine device, 
abstinence, or tubal ligation. In addition, the study medication may have unknown risks to breast-
fed babies. Therefore, study subjects are instructed not to breastfeed while taking the study drug.  
 
Risks of the Assessment: Risks of drawing blood include pain, bruising at the puncture site, swelling, 
feeling faint or lightheaded, and, rarely, infection. 
 
Confidentiality and Loss of Privacy: All efforts will be made to ensure that subject information obtained 
during the course of this study will be kept confidential. However, we cannot guarantee total privacy. 
Personal information may be given out if required by law.   
 
13.1.1 Protections Against Risks.  
Weight Loss Intervention: Subjects will be informed of all potential risks when providing consent before 
enrolling in the study. They will be able to withdraw from the study at any time. Risk of gallbladder disease 
will be minimized by limiting weight loss to no more than 3 lb. per week for 3 consecutive weeks. Subjects 
who exceed this limit will be advised to increase their calorie intake.  
 
Study Medication: As in previous studies conducted at the Center, e.g., 58, 59, 79, 82, 112 we will make every 
attempt to minimize, assess, and manage the occurrence of any side effect or adverse event (AE) of the 
study medication. Subjects will be screened for medical conditions that would preclude the use of 
phentermine, and stringent exclusionary criteria will be employed to limit the possibility of AEs (see above). 
Subjects will be informed about the possibility of medication side effects, including symptoms of rare but 
serious conditions, during informed consent and prior to randomization to medication or placebo (for 
randomization-eligible subjects who lose < 2% after 4 weeks of BT). A list of the subject’s current 
medications will be collected during the screening, and subjects will be asked to inform study staff before 
starting any new medication during the course of the study.  
To reduce the likelihood of side effects, randomized subjects will be taught how to properly perform 
the subcutaneous injection of the study medication (phentermine or placebo), and the medication will be 
initiated at 0.6 mg/day and increased by 0.6 mg at weekly intervals until a dosage of 3.0 mg/day is achieved. 
Subjects who do not tolerate an increased dose during escalation will delay escalation by up to 7 days. 
Subjects will be instructed, if they miss a dose, to resume the once-daily regimen with the next scheduled 
dose and not to take an extra or higher dose. If they miss more than 3 days, they will be instructed to call 
the study medical staff who will re-initiate therapy at 0.6 mg/day to avoid gastrointestinal symptoms. 
Subjects will be taught how to properly store the medication and dispose of needles.  
Randomized subjects will be asked to report any new symptoms to the research staff. In addition to 
assessment visits, randomized subjects will have a brief medical visit (10-15 minutes) with study staff (e.g., 
registered nurse) at week 2 (after initiation of the medication) and week 6 (after most subjects will have 
completed dose escalation) to monitor response to the medication. Side effects will be queried during every 


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study visit, and the study NP or physician will be available to assess the subject and evaluate and treat any 
adverse events. Subjects will be encouraged to contact study staff immediately should an AE occur 
between visits, and 24-hour contact information will be provided for study personnel and the study 
physician. If any AE requires treatment follow-up, subjects will be provided with appropriate referrals. For 
all non-study-related medical events, subjects will be referred to their own primary care provider. 
During outcome assessments and brief medical visits, patients will be asked about their mood or any 
thoughts of harming themselves through administration of the Columbia-Suicide Severity Rating Scale. 
Additionally, online questionnaires assessing depressive symptoms will be checked within 24 hours of their 
completion for signs of severe depression, including suicidal ideation. (Participation in a weight loss 
program is not a risk factor for depression and typically results in improvements in mood. 113) In the event 
of mental health events, subjects will be referred to the study’s psychologist or psychiatrist for further 
evaluation to determine if clinical intervention is needed (i.e., referral to a mental health provider).  
Subjects of childbearing potential will provide a urine pregnancy test during their initial assessment 
and again prior to randomization to a study medication and must agree in writing to use an approved method 
of contraception throughout the study. Approved methods include the use of double barrier methods 
(condom with spermicide or diaphragm with spermicide), stable hormonal contraception, intrauterine 
device, abstinence, or tubal ligation. Subjects will be asked to immediately notify the study team, 
discontinue the drug (if applicable), and consult with an obstetrician if they become pregnant during the 
study. Subjects who become pregnant will be withdrawn from the study medication and BT treatment. The 
study physician or NP will follow up with any such patients during pregnancy and after childbirth to assess 
adverse events.  
Randomized subjects will have the option to stop taking study medication at any time. The PI or study 
physician may also withdraw a subject from the medication if medically appropriate. Stopping study 
medication will not preclude subjects’ completion of the BT program (unless weight loss is contraindicated).  
 
Confidentiality and Loss of Privacy: All applicable national and international guidelines, regulations, 
and Institutional Review Board (IRB) guidelines regarding subject privacy and confidentiality will be followed 
throughout the study. No identifying information will be included with stored research data, biological 
samples, clinical data, or reports of results. Penn network firewalls prevent unauthorized internal access to 
data, external access to data, and malicious intent to destroy data and systems. Controlled user access will 
ensure that only appropriate and authorized personnel are able to view, access, and modify study data. 
Data sent to the IRB, Investigational Drug Services, or the Data and Safety Monitoring Board will contain 
no identifying information, except as required when reporting AEs. Password-protected files linking subject 
names and ID numbers will only be accessible to the PI and research coordinator, and will be stored in a 
locked office. Publications will be based on analyses of de-identified data, and subject ID numbers will only 
be included if necessary to clarify an individual patient event. Patient privacy will be protected by conducting 
all assessments and treatment visits in closed examination rooms or offices, where only the patient and 
appropriate staff member are present. Subjects will not be video or audiotaped at any point during the study.  
 
Biological Sample Storage: All samples and medication will kept in a secure refrigeration room 
accessible only to relevant study staff. Biological samples stored for later analysis will be labeled with the 
patient ID and relevant assessment code, and, after being centrifuged and separated, will be frozen at −80 
°C. 
13.2 Benefits 
All subjects will receive 7 months of intensive behavioral weight loss treatment. Previous studies suggest 
that the average patient will achieve losses of 5-8% of initial weight and corresponding improvements in 
cardiometabolic risk factors (e.g., blood pressure, waist circumference, HDL cholesterol, triglycerides, 
glucose). Early non-responders to BT, who are unlikely to experience these benefits with continued BT 
alone, may be more likely to achieve these outcomes when medication is added to BT. This study will inform 
clinical best practice recommendations for prescribing BT or obesity pharmacotherapy by identifying 
characteristics of individuals who are not likely to lose weight with BT alone and providing preliminary data 
regarding whether such individuals benefit from the addition of obesity medication. These data could 
ultimately result in the development of algorithms that match obesity treatment methods to patient 
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13.3 Risk Benefit Assessment 
The anticipated risks of the study are minimal, and the potential benefits outweigh the risks. 
13.4 Informed Consent Process / HIPAA Authorization  
All applicants will be screened by phone to determine whether they potentially meet eligibility criteria. We 
will obtain a waiver of written documentation of consent for the telephone screen. Initially-eligible individuals 
will be invited for an in-person screening visit that will include a behavioral evaluation conducted by a 
psychologist (including the PI) and a medical history. These assessments will take place individually in staff 
offices and medical assessment rooms, respectively, to ensure patient privacy.  During the behavioral 
evaluation, psychologists will explain the study procedures and possible risks and benefits associated with 
participation, including possible assignment to study medication or placebo during the randomized phase 
of the trial. Psychologists will inform subjects that their participation in the study is voluntary and that they 
will not lose any benefits to which they are otherwise entitled by choosing not to participate. They will offer 
to provide suggestions for alternative weight control programs if the individual chooses not to participate. 
After reviewing all study procedures, the subject will be given the opportunity to ask questions and additional 
time to review consent forms, if desired. The psychologist will obtain a signed consent and HIPAA 
authorization from interested and eligible subjects. Subjects will receive a copy of the combined 
consent/HIPAA form. The original signed consent/HIPAA forms will be stored in a regulatory consent binder. 
Final eligibility for enrollment will be determined by results of the behavioral evaluation, medical history, 
urine pregnancy test, and blood panel analysis.  
At the randomization visit, trained research staff will review with subjects eligible for randomization 
(i.e., those who lose < 2% after 4 weeks of BT) information related to the study medication, including 
possible risks and benefits, and will confirm applicants’ willingness to participate prior to enrolling them in 
the randomized phase of the trial.  
14 Study Finances 
14.1 Funding Source 
We anticipate receiving funding for this study from the National Institute of Diabetes and Digestive and 
Kidney Diseases (NIDDK)’s K23 Mentored Patient-Oriented Research Career Development Award 
(Independent Clinical Trial Required) for the application “Improving Weight Loss in Early Non-responders 
to Behavioral Treatment” (K23DK116935-01A1). 
14.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
14.3 Subject Stipends or Payments 
Subjects will receive $75 after completing the post-treatment assessment visit (week 24) for the subject’s 
time and effort of being in the trial. 
15 Publication Plan 
We will register the study with a publicly assessable database such as clinicaltrials.gov. The PI holds the 
primary responsibility for publication of the results of the study. An initial report of the findings will be 
presented at an annual scientific meeting (e.g., The Obesity Society, The Society for the Study of Ingestive 
Behavior, The Society for Behavior Medicine). We plan to publish the study results approximately 6 months 
after study completion in an appropriate journal (e.g., the New England Journal of Medicine, Obesity, 
International Journal of Obesity). Secondary papers will include an examination of behavioral and 
psychosocial predictors of weight loss. 
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increased body mass index." PLoS medicine 1.3 (2004): e62. 
 
 
 
17 Attachments 
• Sample Consent Form 
• Questionnaire Measures