Obesity
Conditions
Keywords
Semaglutide, Body weight, Obesity, weight loss, medication, overweight, lifestyle modification, diet, exercise, Body Weight Changes, Appetitive Behavior
Brief summary
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.
Detailed description
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.
Interventions
BEHAVIORALBehavioral Treatment
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.
DRUGPlacebo
An inactive saline solution administered via subcutaneous injection
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
Sponsors
University of Pennsylvania
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Study 1 is a double-blind, placebo-controlled, randomized controlled, long-term treatment trial. Study 2 is a double-blind, medication withdrawal trial, re-randomized treatment trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women who report a desire to lose weight 2. Aged 18-70 years 3. Body mass index \[BMI\] ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with an obesity-related comorbidity (e.g., treated or untreated hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) 4. 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 5. Subjects must * Plan to remain in the Philadelphia area for the next 1.5 years. * Ability to provide informed consent before any trial-related activities.
Exclusion criteria
1. A diagnosis of type I or II diabetes 2. Hemoglobin A1c (HbA1c) \> 6.5% 3. Uncontrolled hypertension (blood pressure ≥ 160/100 mm Hg) 4. Clinically significant hepatic (i.e., liver fibrosis, cirrhosis or confirmed NASH) or renal disease 5. Uncontrolled thyroid disease 6. Experienced a cardiovascular event (e.g., stroke, myocardial infarction) in the last 6 months, congestive heart failure, or heart block greater than first degree 7. A history of acute pancreatitis in the last 6 months 8. Any history of chronic pancreatitis 9. A history of malignancy (other than non-melanoma skin cancer) within the last 5 years 10. A personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 11. A self-reported change in body weight \>5kg (11 lbs) within 90 days before screening 12. Used within the last 6 months medications known to produce weight loss/gain (e.g., medications approved for weight loss, oral steroids, antipsychotic medications) or any GLP-1 receptor agonist. 13. Known or suspected allergy or hypersensitivity to trial medication(s), excipients, or related products 14. The receipt of any investigational drug within 6 months prior to this trial 15. Applicants with current severe major depressive disorder (BDI-II score ≥ 29 or Patient Health Questionnaire-9 \[PHQ-9\] score \> 15) or severe anxiety disorder 16. Applicants with current, active suicidal ideation, and/or a suicide attempt within the past year (such individuals will be referred for psychiatric treatment if they have not previously received it). 17. Any severity of psychotic or bipolar disorder 18. Bulimia nervosa diagnosis within the past 5 years 19. Self-reported alcohol or substance abuse within the past 6 months, including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per week) 20. History of (or plans to receive in the next 1.5 years) bariatric surgery or a weight loss device. (However, the following will be allowed: liposuction or abdominoplasty \> 1 year before screening, laparoscopic banding if removed \> 1 year before screening, intragastric balloon or aspire assist if removed \> 1 year before screening.) 21. Inability to walk 5 blocks or more (comfortably) or engage in another form of aerobic activity. 22. Women who are nursing, pregnant, or planning to become pregnant in the next 1.5 years or are not using adequate contraceptive measures 23. Previous participation in this trial (e.g., randomized but failed to participate) 24. Changes to any chronic medication (type or dosage) within the past 3 months. 25. Food allergy or dietary preference that would prevent the individual from consuming the standard breakfast or ad libitum lunch. 1\. To be eligible to participate in the re-randomized treatment period from weeks 60 to 72, subjects must also: * complete a week 60 assessment * be classified as "on drug" as at the week 60 assessment and report taking at least one dose of trial product within the past 2 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Study 1 Ad Libitum Energy Intake (kcal) During a Buffet Lunch Meal (4 Hrs After Standardized Breakfast) | S1: Change from baseline to weeks 20, 40, and 60 | Primary outcome (Study 1) |
| Study 2 Ad Libitum Energy Intake (kcal) During a Buffet Lunch Meal (4 Hrs After Standardized Breakfast) | S2: Endpoint comparison at week 72 | Primary outcome (Study 2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Study 1 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) When Fasting | S1: Change from baseline to weeks 20, 40, and 60 | 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). |
| 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) | S1: Change from baseline to weeks 20, 40, and 60 | 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). |
| Study 1 Past-week Hunger as Measured Using the Control of Eating Questionnaire (COEQ) | S1: Change from baseline to weeks 20, 40, and 60 | 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. |
| Study 1 Past-week Fullness After Meals as Measured Using the Control of Eating Questionnaire (COEQ) | S1: Change from baseline to weeks 20, 40, and 60 | 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. |
| Study 1 Past-week Food Preoccupation as Measured Using the Control of Eating Questionnaire (COEQ) | S1: Change from baseline to weeks 20, 40, and 60 | 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. |
| Study 1 Explicit Responsiveness to the Food Environment (Power of Food Scale 15-item Version) | S1: Change from baseline to weeks 20, 40, and 60 | 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. |
| Study 1 Implicit Food Wanting of High-fat, Savory Foods Measured Using the Leeds Food Preference Task | S1: Change from baseline to weeks 20, 40, and 60 | 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. |
| Study 2 Laboratory-based Appetite Measured as a Composite of Visual Analogue Scale Ratings (Hunger, Fullness, Satiety, Prospective Consumption) When Fasting | S2: Week 72 endpoint controlling for S1 baseline | 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). |
| 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) | S2: Week 72 endpoint controlling for S1 baseline | 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). |
| Study 2 Past-week Hunger as Measured Using the Control of Eating Questionnaire (COEQ) | S2: Week 72 endpoint controlling for S1 baseline | 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. |
| Study 2 Past-week Fullness After Meals as Measured Using the Control of Eating Questionnaire (COEQ) | S2: Week 72 endpoint controlling for S1 baseline | 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. |
| Study 2 Past-week Food Preoccupation as Measured Using the Control of Eating Questionnaire (COEQ) | S2: Week 72 endpoint controlling for S1 baseline | 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. |
| Study 2 Explicit Responsiveness to the Food Environment (Power of Food Scale 15-item Version) | S2: Week 72 endpoint controlling for S1 baseline | 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. |
| Study 2 Implicit Food Wanting of High-fat, Savory Foods Measured Using the Leeds Food Preference Task | S2: Week 72 endpoint controlling for S1 baseline | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between July 2022 and February 2024 via print and social media advertisements.
Pre-assignment details
We sought to capitalize on the long-term design of Study 1 by conducting a separate, 12-week, medication withdrawal trial (Study 2) to compare subjects who discontinued semaglutide 2.4 mg to those who had never received active medication (continuous placebo). A very small number of subjects were randomized to continue taking semaglutide at week 60 to maintain blinding. Number of continued subjects was not sufficient for statistical comparison and their Study 2 results are not reported.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 44.2 Years STANDARD_DEVIATION 12.7 |
| Body weight | 106.9 kg STANDARD_DEVIATION 21.4 |
| Lunch intake | 1050.6 kcal STANDARD_DEVIATION 358.9 |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black | 26 Participants |
| Race/Ethnicity, Customized Both Hispanic and Middle Eastern/Arab | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 6 Participants |
| Race/Ethnicity, Customized Middle Eastern/Arab | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Middle Eastern/Arab | 105 Participants |
| Race/Ethnicity, Customized Other or more than one | 2 Participants |
| Race/Ethnicity, Customized White | 86 Participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 72 | 0 / 20 | 0 / 43 | 0 / 10 |
| other Total, other adverse events | 42 / 48 | 70 / 72 | 6 / 20 | 17 / 43 | 3 / 10 |
| serious Total, serious adverse events | 0 / 48 | 3 / 72 | 0 / 20 | 0 / 43 | 0 / 10 |
Outcome results
None listed