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

Sponsor

University of Pennsylvania (Other)

Overall Status

Recruiting

CT.gov ID

NCT03779048

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

150

Enrollment

Location

Arms

43.5

Anticipated Duration (Months)

3.4

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Obesity	Behavioral: Behavioral Treatment Drug: Placebo Drug: Phentermine 15 MG	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Phase 1 is observational. Phase 2 is a double-blind, placebo-controlled, randomized controlled trial.Phase 1 is observational. Phase 2 is a double-blind, placebo-controlled, randomized controlled trial.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Double-blind

Primary Purpose:

Treatment

Official Title:

Use of Pharmacotherapy to Improve Weight Loss in Early Non-responders to Behavioral Treatment

Actual Study Start Date :

Jul 15, 2019

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Behavioral Treatment + Placebo All participants will complete an initial 4-week behavioral treatment (BT) run-in. 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.	Behavioral: Behavioral Treatment 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). Other Names: Lifestyle modification Behavioral weight loss Drug: Placebo The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill. Other Names: Placebo for medication
Active Comparator: Behavioral Treatment + Medication All participants will complete an initial 4-week behavioral treatment (BT) run-in. 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.	Behavioral: Behavioral Treatment 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). Other Names: Lifestyle modification Behavioral weight loss Drug: Phentermine 15 MG The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill. Other Names: Medication

Arm

Intervention/Treatment

Active Comparator: Behavioral Treatment + Placebo

All participants will complete an initial 4-week behavioral treatment (BT) run-in. 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.

Behavioral: Behavioral Treatment

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).

Other Names:

Lifestyle modification

Behavioral weight loss

Drug: Placebo

The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill.

Other Names:

Placebo for medication

Active Comparator: Behavioral Treatment + Medication

Behavioral: Behavioral Treatment

Other Names:

Lifestyle modification

Behavioral weight loss

Drug: Phentermine 15 MG

The study medication (placebo or phentermine 15.0 mg) is a once-daily self-administered pill.

Other Names:

Medication

Outcome Measures

Primary Outcome Measures

Phase 1: Percent weight loss [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, based on percent weight loss [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 = [(fasting rating before preload - 60 min post-preload rating)] / (energy content of preload) x 100. [Baseline (week -5)]
Primary predictor variable - phase 1
Phase 1: Baseline postprandial change in GLP-1 during a test meal [Baseline]
Primary predictor variable - phase 1
Phase 1: Baseline gastric emptying during a test meal (acetaminophen test) [Baseline]
Primary predictor variable - phase 1
Phase 2: Percent weight loss [Week 0 (randomization) to week 24]
Primary outcomes - phase 2

Secondary Outcome Measures

Phase 1: Baseline hunger, as measured by visual analogue scales (range 0-100 mm, higher = more hunger) during a test meal [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline relative reinforcing value of food (computer task), number of food reinforcer points earned [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline delay discounting (computer task), area under the curve representing the ratio of immediate reward size to time delay [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline implicit wanting of food, reaction time on Leeds Food Preference Questionnaire [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline fasting ghrelin [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline fasting leptin [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline postprandial change in insulin during a test meal [Baseline]
Secondary predictor variable - phase 1
Phase 1: Baseline postprandial change in peptide YY during a test meal [Baseline]
Secondary predictor variable - phase 1
Phase 2: Weight loss (kg) [Week 0 (randomization) to week 24]
Secondary outcomes - phase 2
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]
Secondary outcomes - phase 2
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]
Secondary outcomes - phase 2
Phase 2: Change in satiety, as measured by visual analogue scales (range 0-100 mm) during a test meal; satiety quotient = [(fasting rating before preload - 60 min post-preload rating)] / (energy content of preload) x 100. [Week 0 (randomization) to week 24]
Secondary outcomes - phase 2
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]
Secondary outcomes - phase 2
Phase 2: Change in relative reinforcing value of food (computer task), number of food reinforcer points earned [Week 0 (randomization) to week 24]
Secondary outcomes - phase 2
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]
Secondary outcomes - phase 2

Other Outcome Measures

Phase 1: Baseline eating behavior as measured by The Eating Inventory (EI); Dietary restraint subscale (scored 0-21 higher=more restraint), Disinhibition sub scale (scored 0-16 higher=more disinhibition), Hunger sub scale (scored 0-14 higher=more hunger) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline appetite ratings (ratings of appetite during the past week using visual analogue scales, scored 0-100 mm, higher=greater amount or frequency) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline reinforcing value of food as measured by the Power of Food Scale (PFS; range 1-5, higher=greater power of food) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline sensitivity to reward as measured by the Behavioral Inhibition/Activation Scale (BIS/BAS) (BIS subscale range 7-28, higher = greater inhibition; BAS reward responsiveness sub scale range 5-20, higher=greater reward responsiveness, etc) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline impulsivity as measured by The Barratt Impulsiveness Scale (BIS-15, range 15-60, higher= more impulsiveness) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline binge eating as measured by The Questionnaire on Eating and Weight Patterns (QEWP-5); Measure categorizes participants based on whether they may meet diagnostic criteria for binge eating disorder [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline craving frequency as measured by the Food Craving Q Trait - Reduced [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline emotional eating as measured by the Dutch Eating Behaviour Questionnaire (DEBQ) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline perceived barriers to healthy eating and physical activity (Scale by Welsh et al., 2012) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline Weight Efficacy Life-Style Questionnaire (WEL) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline SCI Exercise Self Efficacy Scale (ESES) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Randomization Ball and Crawford Social Support Scale [Randomization (week 0)]
Exploratory predictor variable - phase 1
Phase 1: Baseline food addiction using the Yale Food Addiction Scale (YFAS) [Baseline]
Exploratory predictor variable - phase 1
Phase 1: The reinforcing efficacy of high- and low-calorie food [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline sleep hours survey [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline Perceived Stress Scale [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline anxiety as measured by the GAD-7 [Baseline]
Exploratory predictor variable - phase 1
Phase 1: Baseline general mindfulness and acceptance as measured using the Philadelphia Mindfulness Scale [Baseline]
Exploratory predictor variable - phase 1
Phase 2: Change in blood pressure [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in pulse [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in waist circumference [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in triglycerides [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in HDL and LDL cholesterol [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in fasting blood sugar [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in appetite ratings (ratings of appetite during the past week using visual analogue scales, scored 0-100 mm) [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in quality of life as measured by the Impact of Weight on Quality of Life (IWQOL) [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in depressive symptoms as measured by the Patient Health Questionnaire (PHQ-9) [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2
Phase 2: Change in physical activity using the Paffenbarger Physical Activity Questionnaire [Week 0 (randomization) to week 24]
Exploratory outcomes - phase 2

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
Narrow angle glaucoma
Presence or history of marked agitation
Current severe major depressive episode (BDI-II score ≥ 29), current active suicidal ideation, or history of suicide attempts within the past 5 years.
Any severity of thought or bipolar disorder, or bulimia nervosa.
Psychiatric hospitalization within the past 6 months
Self-reported alcohol or substance abuse within the past 6 months, including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per week)
Past year history of drug abuse
Use in the past 2 weeks of monoamine oxidase inhibitors
Current use of serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g. venlafaxine, duloxetine, desvenlafaxine, milnacipran, levomilnacipran).
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)
Loss of ≥ 5% of initial body weight within the past 6 months
History of (or plans for) bariatric surgery (e.g., roux en y gastric bypass, sleeve gastrectomy, gastric banding), endoscopic intragastric balloon, or aspire assist.
Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity (e.g., swimming)
Known or suspected allergy to sympathomimetic amines or related products
The receipt of any investigational drug within 6 months prior to this trial
Previous participation in this trial (e.g., randomized and failed to participate)
Changes to any chronic medication (type or dosage) within the past 3 months.
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:

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.
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.