Use of Medication to Improve Weight Loss in Suboptimal Early Responders to Behavioral Treatment

Subjects will be a total of 150 adults, aged 18-70 years, with a body mass index (BMI) of 32
kg/m2 or above (29 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. Within
2 weeks of this baseline assessment, participants will begin an initial 4-week behavioral
treatment (BT) "run-in" delivered individually in 20-30 minute weekly sessions.

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 CCK 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;
liraglutide 3.0 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
liraglutide 3.0 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 86% power to detect between-treatment group
differences at week 24 of 5% (effect size: d = 0.88).

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, RRVfood, 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.

Inclusion Criteria:

1. BMI ≥ 32 kg/m² (or 29 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

Exclusion Criteria:

1. Pregnant or nursing, or plans to become pregnant in the next 9 months.

2. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia
syndrome type 2

3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood
pressure ≥ 100 mm Hg)

4. Type 1 diabetes

5. Type 2 diabetes

6. A fasting blood glucose < 126 mg/dL

7. Recent history of cardiovascular disease (e.g., myocardial infarction or stroke within
the past 1 year), congestive heart failure, or heart block greater than first degree

8. Clinically significant hepatic or renal disease

9. Thyroid disease, not controlled

10. History of malignancy (except for non-melanoma skin cancer) in past 5 years

11. Current severe major depressive episode (BDI-II score ≥ 29), current active suicidal
ideation, or history of suicide attempts within the past 5 years.

12. Any severity of thought or bipolar disorder, or bulimia nervosa.

13. Psychiatric hospitalization within the past 6 months

14. Self-reported alcohol or substance abuse within the past 6 months, including at-risk
drinking (current consumption of ≥ 14 alcoholic drinks per week)

15. 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)

16. Loss of ≥ 5% of initial body weight within the past 6 months

17. History of (or plans for) bariatric surgery (e.g., roux en y gastric bypass, sleeve
gastrectomy, gastric banding), endoscopic intragastric balloon, or aspire assist.

18. Inability to walk 5 blocks comfortably or engage in some other form of aerobic
activity (e.g., swimming)

19. Known or suspected allergy to trial medication(s), excipients, or related products

20. The receipt of any investigational drug within 6 months prior to this trial

21. Previous participation in this trial (e.g., randomized and failed to participate)

22. History of pancreatitis

23. Changes to any chronic medication (type or dosage) within the past 3 months.

24. 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.

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.

Early BT responders who lose>=2% during the BT run-in will be offered the same 24-week BT
program, but will not receive study medication or be included in the randomized trial.