Use of Pharmacotherapy to Improve Weight Loss in Early Non-responders to Behavioral Treatment
Overview
- Phase
- Phase 4
- Intervention
- Behavioral Treatment
- Conditions
- Obesity
- Sponsor
- University of Pennsylvania
- Enrollment
- 147
- Locations
- 1
- Primary Endpoint
- Phase 1: Percent Weight Loss
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •BMI ≥ 31 kg/m² (or 28 kg/m2 with obesity-related comorbidity)
- •Age ≥ 21 years and ≤ 70 years
- •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).
- •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
- •Pregnant or nursing, or plans to become pregnant in the next 9 months.
- •Uncontrolled hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg)
- •Type 1 diabetes
- •Type 2 diabetes
- •A fasting blood glucose \> 126 mg/dL (on second assessment after first elevated value)
- •History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, or heart block greater than first degree
- •Clinically significant hepatic or renal disease
- •Hyperthyroidism
- •Other thyroid disease, not controlled
- •History of malignancy (except for non-melanoma skin cancer) in past 5 years
Arms & Interventions
Phase 2: Behavioral Treatment + Placebo
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.
Intervention: Behavioral Treatment
Phase 2: Behavioral Treatment + Placebo
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.
Intervention: Placebo
Phase 2: Behavioral Treatment + Medication
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.
Intervention: Behavioral Treatment
Phase 2: Behavioral Treatment + Medication
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.
Intervention: Phentermine 15 MG
Phase 1: 4-week Behavioral Treatment Run-in
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.
Intervention: Behavioral Treatment
Outcomes
Primary Outcomes
Phase 1: Percent Weight Loss
Time Frame: Week -4 (start of BT run-in) to week 0 (randomization)
Co-primary outcomes - phase 1
Phase 1: Number of Participants Who Are Categorized as Early Non-responders at Randomization (Week 0), Based on Percent Weight Loss
Time Frame: Week -4 (start of BT run-in) to week 0 (randomization)
Co-primary outcomes - phase 1
Phase 1: Baseline Satiety, as Measured by Visual Analogue Scales (Range 0-100 mm) During a Test Meal; Satiety Quotient = [(Post-preload Rating - Fasting Rating Before Preload)] / (Energy Content of Preload in kcal) x 100.
Time Frame: Baseline (week -5)
Primary predictor variable - phase 1 Appetite suppression was first calculated as the average of 100 mm VAS items: hunger (reverse score), satisfaction, fullness, and prospective consumption (reverse score), such that higher scores indicate more appetite suppression (less appetite) for each test meal rating (fasting, then every 10m for 60m). The satiety quotient was then calculated for each post-preload rating using the above formula (see measure title). More positive scores show increased satiety (more appetite suppression). The final analysis uses the 60-minute area under the curve (AUC) for the satiety quotient to predict phase 1 weight loss outcomes. Area under the curve is calculated using the trapezoidal rule to sum the area under each 10-minute interval. AUC = Σ i = 0 to i = 60 10min\*(x(i) + x(i-1))/2) where x is the satiety quotient value at time i. Higher scores indicate higher sustained satiety.
Phase 1: Baseline Postprandial Change in GLP-1 During a Test Meal
Time Frame: Baseline
Primary predictor variable - phase 1. Blood samples were drawn at time 0 (fasting) and 30- and 60-min postprandial samples after consumption of a test meal. Value presented below is the 60-minute incremental area under the curve (AUC) for GLP-1 in picomoles (pM). Area under the curve is calculated using the trapezoidal rule to sum the area under each 0.5-hour interval. AUC = Σ i = 0 to i = 1 0.5hr\*(x(i) + x(i-1))/2) where x is the GLP-1 value in pM at time i.
Phase 1: Baseline Gastric Emptying During a Test Meal (Acetaminophen Test)
Time Frame: Baseline
Primary predictor variable - phase 1 Gastric emptying was measured as the 60-minute area under the curve (AUC) for acetaminophen in micrograms per milliliter (ug/mL). Blood samples were obtained at time 0 (fasting/no acetaminophen - confirmatory) and 30 and 60-min after ingestion. 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. Area under the curve is calculated using the trapezoidal rule to sum the area under each 0.5-hour interval. AUC = Σ i = 0 to i = 1 0.5hr\*(x(i) + x(i-1))/2) where x is the acetaminophen value in ug/mL at time i.
Phase 2: Percent Weight Loss
Time Frame: Week 0 (randomization) to week 24
Primary outcomes - phase 2 Percent change from randomization in body weight
Secondary Outcomes
- Phase 1: Baseline Postprandial Change in Insulin During a Test Meal(Baseline)
- Phase 1: Baseline Hunger, as Measured by Visual Analogue Scales (Range 0-100 mm, Higher = More Hunger) During a Test Meal(Baseline)
- Phase 1: Baseline Relative Reinforcing Value of Food (Computer Task), Number of Food Reinforcer Points Earned(Baseline)
- Phase 1: Baseline Delay Discounting (Computer Task), Area Under the Curve Representing the Ratio of Immediate Reward Size to Time Delay(Baseline)
- Phase 1: Baseline Implicit Wanting, Reaction Time on Leeds Food Preference Questionnaire(Baseline)
- Phase 1: Baseline Fasting Leptin(Baseline)
- Phase 1: Baseline Fasting Ghrelin(Baseline)
- Phase 1: Baseline Postprandial Change in Peptide YY During a Test Meal(Baseline)
- Phase 2: Weight Loss (kg)(Week 0 (randomization) to week 24)
- Phase 2: Number of Participants With a Weight Loss of 5% or Greater of Randomization Body Weight at Week 24(Week 0 (randomization) to week 24)
- Phase 2: Number of Participants With a Weight Loss of 10% or Greater of Randomization Body Weight at Week 24(Week 0 (randomization) to week 24)
- Phase 2: Change in Appetite Suppression, as Measured by Visual Analogue Scales (Range 0-100 mm) During a Test Meal(Week 0 (randomization) to week 24)
- Phase 2: Change in Hunger, as Measured by Visual Analogue Scales (Range 0-100 mm, Higher=More Hunger) During a Test Meal(Week 0 (randomization) to week 24)
- Phase 2: Change in Delay Discounting (Computer Task), Area Under the Curve Representing the Ratio of Immediate Reward Size to Time Delay(Week 0 (randomization) to week 24)