This study will evaluate the effect of semaglutide on eating behavior, appetite (hunger/fullness), and food liking in the long-term, as compared to placebo. All participants will receive lifestyle modification (diet and exercise) counseling, and will be prescribed the FDA-approved weight loss medication, semaglutide, or placebo (an inactive saline solution) for 72 weeks.
This trial consists of a single 72-week treatment period during which two studies will be conducted. Study 1 (i.e., long-term treatment trial; weeks 0-60) is a 60-week, single center, double-blinded, randomized controlled, parallel group design trial, and Study 2 (i.e., re-randomized medication withdrawal trial; weeks 60-72) is a separate, 12-week, double-blind, re-randomized medication withdrawal trial. The long-term treatment trial (Study 1) will randomly assign (in a 3:2 semaglutide:placebo ratio) 120 subjects with a body mass index (BMI) ≥30 kg/m2, or ≥27 kg/m2 with ≥1 obesity-related co-morbidities, to 60 weeks of: 1) placebo with moderate intensity lifestyle intervention (as used in STEP 1); or 2) semaglutide 2.4 mg with the same lifestyle intervention. All subjects will receive 60 weeks of trial product, which will be up-titrated over 16 weeks in those assigned to semaglutide 2.4 mg. They will complete assessments of energy intake, appetite, food reward, mood, symptoms of disordered eating, and anthropomorphic measurements at baseline (week 0) and weeks 20, 40, and 60. The primary aim in the initial long-term treatment trial will be to compare the long-term effect of semaglutide 2.4 mg vs placebo on ad libitum energy intake during a lunch meal at weeks 20, 40, and 60. Confirmatory secondary aims will test the effect of semaglutide 2.4 mg at weeks 20, 40 and 60 on subjective appetite ratings (both measured during a standardized breakfast in the lab and as experienced more globally over the past week), explicit food reward, as measured with the Power of Food Scale (24), and implicit food reward, as measured with the Leeds Food Preference Task (25, 26). Measures of food cravings, mood, eating disorder symptoms, and self-report measures of eating behavior will be considered supportive secondary endpoints and will provide additional evidence of the medication's safety and efficacy. Following the completion of Study 1 at week 60, all subjects who complete a week 60 assessment and remain on drug will be enrolled in Study 2. Semaglutide-treated subjects will be re-randomized (in a 1:4 semaglutide:placebo ratio) to receive semaglutide 2.4 mg or placebo for 12 weeks. All subjects originally assigned to placebo will continue with that medication for an additional 12 weeks. Both researchers and subjects will remain blinded to subjects' original and re-randomized (or continued) treatment assignments. The goal of this re-randomized medication withdrawal period will be to compare the 80% of subjects originally assigned to semaglutide 2.4 mg who receive placebo at week 60 (semaglutide-to-placebo group) to the subjects originally randomized to placebo (continuous-placebo group) on all primary and secondary outcome measures at week 72 (after controlling for Study 1 baseline/week 0 values). All subjects will terminate trial product at cumulative week 72 and will return to clinic for a final safety visit at week 76. Outcome assessments including ad libitum energy intake, subjective measures of appetite, food reward, eating behavior, mood, and eating disorder symptoms will occur at weeks 0, 20, 40, and 60 of Study 1 and at week 12 (72 weeks from original randomization) of the re-randomized treatment period. Measurements of body weight, waist circumference, blood pressure, pulse, and global, past-week appetite and food cravings (COEQ) also will be collected every 4 weeks throughout both treatment studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
120
All participants, regardless of medication assignment, will receive the same 60-week behavioral weight loss program. Brief (15-minute), individual lifestyle counseling sessions will be delivered by a psychologist, behavioral health counselor, or registered dietitian (or other trained health care provider) at weeks 0 (i.e., baseline/randomization), 2, 4 and every fourth week from week 4 to week 60 (17 sessions) of Study 1. 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 ≥250 lb). They will be instructed to engage in low-to-moderate intensity physical activity (e.g., walking), gradually building to a goal of ≥150 minutes per week (spread across 5 days) by week 40. They will be instructed to use calorie counting and self-monitoring to meet their goals.
An inactive saline solution administered via subcutaneous injection
University of Pennsylvania Center for Weight and Eating Disorders
Philadelphia, Pennsylvania, United States
Study 1 Ad Libitum Energy Intake (kcal) During a Buffet Lunch Meal (4 Hrs After Standardized Breakfast)
Primary outcome (Study 1)
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 2 Ad Libitum Energy Intake (kcal) During a Buffet Lunch Meal (4 Hrs After Standardized Breakfast)
Primary outcome (Study 2)
Time frame: S2: Endpoint comparison at week 72
Study 1 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) When Fasting
Secondary confirmatory outcome (Study 1): This is a single value calculated by averaging 100-mm VAS ratings for hunger (reversed), fullness, satiety, and prospective food consumption (reversed) as measured when fasting prior to eating a standardized breakfast. Score range 0-100 mm. Higher values indicate greater suppression (i.e., less appetite).
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) After Eating (Area Under the Curve)
Secondary confirmatory outcome (Study 1): This is a single value calculated by averaging 100-mm VAS ratings for hunger (reversed), fullness, satiety, and prospective food consumption (reversed) as measured every 30 minutes in the 4 hours after eating a standardized breakfast. Post-prandial scores were combined into a single area under the curve value using the trapezoidal method. Possible area range: 0 - 24,000. Higher values indicate greater suppression (i.e., less appetite).
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Past-week Hunger as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 1): Visual analogue scale rating of hunger during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater hunger.
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Semaglutide 2.4 mg is a once weekly subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonist that has been FDA approved for weight loss
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Past-week Fullness After Meals as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 1): Visual analogue scale rating of fullness after meals during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater fullness after meals.
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Past-week Food Preoccupation as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 1): Visual analogue scale rating of food preoccupation during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater food preoccupation.
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Explicit Responsiveness to the Food Environment (Power of Food Scale 15-item Version)
Secondary confirmatory outcome (Study 1): Explicit responsiveness to the food environment measured by the summary score of the Power of Food Scale (15-item version). Score range 1-5. Higher scores indicate greater responsiveness to the food environment.
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 1 Implicit Food Wanting of High-fat, Savory Foods Measured Using the Leeds Food Preference Task
Secondary confirmatory outcome (Study 1): Implicit food wanting of high-fat, savory foods measured using the Leeds Food Preference Task. Scores range from -100 to +100 with higher scores indicating a greater implicit wanting of high-fat savory foods.
Time frame: S1: Change from baseline to weeks 20, 40, and 60
Study 2 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) When Fasting
Secondary confirmatory outcome (Study 2): This is a single value calculated by averaging 100-mm VAS ratings for hunger (reversed), fullness, satiety, and prospective food consumption (reversed) as measured when fasting prior to eating a standardized breakfast. Score range 0-100 mm. Higher values indicate greater suppression (i.e., less appetite).
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) After Eating (Area Under the Curve)
Secondary confirmatory outcome (Study 2): This is a single value calculated by averaging 100-mm VAS ratings for hunger (reversed), fullness, satiety, and prospective food consumption (reversed) as measured every 30 minutes in the 4 hours after eating a standardized breakfast. Post-prandial scores were combined into a single area under the curve value using the trapezoidal method. Possible area range: 0 - 24,000. Higher values indicate greater suppression (i.e., less appetite).
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Past-week Hunger as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 2): Visual analogue scale rating of hunger during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater hunger.
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Past-week Fullness After Meals as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 2): Visual analogue scale rating of fullness after meals during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater fullness after meals.
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Past-week Food Preoccupation as Measured Using the Control of Eating Questionnaire (COEQ)
Secondary confirmatory outcome (Study 2): Visual analogue scale rating of food preoccupation during the past week (Control of Eating Questionnaire; COEQ). Score range 0-100 mm. Higher scores indicate greater food preoccupation.
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Explicit Responsiveness to the Food Environment (Power of Food Scale 15-item Version)
Secondary confirmatory outcome (Study 2): Explicit responsiveness to the food environment measured by the summary score of the Power of Food Scale (15-item version). Score range 1-5. Higher scores indicate greater responsiveness to the food environment.
Time frame: S2: Week 72 endpoint controlling for S1 baseline
Study 2 Implicit Food Wanting of High-fat, Savory Foods Measured Using the Leeds Food Preference Task
Secondary confirmatory outcome (Study 2): Implicit food wanting of high-fat, savory foods measured using the Leeds Food Preference Task. Scores range from -100 to +100 with higher scores indicating a greater implicit wanting of high-fat savory foods.
Time frame: S2: Week 72 endpoint controlling for S1 baseline