Clinical trial NCT03779048: Use of Medication to Improve Weight Loss in Suboptimal Early Responders to Behavioral Treatment
Official title: Use of Pharmacotherapy to Improve Weight Loss in Early Non-responders to Behavioral Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Obesity
Keywords: phentermine
Hypoglycemic agents
Incretins
Hormones
Appetitive Behavior
Appetite Depressants
Anti-Obesity Agents
Weight Loss
Body Weight
Body Weight Changes
Signs and Symptoms
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2018-12-19
Enrollment: 147
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1 is observational. Phase 2 is a double-blind, placebo-controlled, randomized controlled trial.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. BMI ≥ 31 kg/m² (or 28 kg/m2 with obesity-related comorbidity)
2. Age ≥ 21 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. Uncontrolled hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg)
3. Type 1 diabetes
4. Type 2 diabetes
5. A fasting blood glucose \> 126 mg/dL (on second assessment after first elevated value)
6. History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, or heart block greater than first degree
7. Clinically significant hepatic or renal disease
8. Hyperthyroidism
9. Other thyroid disease, not controlled
10. History of malignancy (except for non-melanoma skin cancer) in past 5 years
11. Narrow angle glaucoma
12. Presence or history of marked agitation
13. Current severe major depressive episode (BDI-II score ≥ 29), current active suicidal ideation, or history of suicide attempts within the past 5 years.
14. Any severity of thought or bipolar disorder, or bulimia nervosa.
15. Psychiatric hospitalization within the past 6 months
16. Self-reported alcohol or substance abuse within the past 6 months, including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per week)
17. Past year history of drug abuse
18. Use in the past 2 weeks of monoamine oxidase inhibitors
19. Current use of serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g. venlafaxine, duloxetine, desvenlafaxine, milnacipran, levomilnacipran).
20. 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)
21. Loss of ≥ 5% of initial body weight within the past 6 months
22. History of (or plans for) bariatric surgery (e.g., roux en y gastric bypass, sleeve gastrectomy, gastric banding), endoscopic intragastric balloon, or aspire assist.
23. Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity (e.g., swimming)
24. Known or suspected allergy to sympathomimetic amines or related products
25. The receipt of any investigational drug within 6 months prior to this trial
26. Previous participation in this trial (e.g., randomized and failed to participate)
27. Changes to any chronic medication (type or dosage) within the past 3 months.
28. 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.

Primary outcomes:
measure: Phase 1: Percent Weight Loss
timeFrame: Week -4 (start of BT run-in) to week 0 (randomization)
measure: Phase 1: Number of Participants Who Are Categorized as Early Non-responders at Randomization (Week 0), Based on Percent Weight Loss
timeFrame: Week -4 (start of BT run-in) to week 0 (randomization)
measure: 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.
timeFrame: Baseline (week -5)
measure: Phase 1: Baseline Postprandial Change in GLP-1 During a Test Meal
timeFrame: Baseline
measure: Phase 1: Baseline Gastric Emptying During a Test Meal (Acetaminophen Test)
timeFrame: Baseline
measure: Phase 2: Percent Weight Loss
timeFrame: Week 0 (randomization) to week 24
Secondary outcomes:
measure: Phase 1: Baseline Hunger, as Measured by Visual Analogue Scales (Range 0-100 mm, Higher = More Hunger) During a Test Meal
timeFrame: Baseline
measure: Phase 1: Baseline Relative Reinforcing Value of Food (Computer Task), Number of Food Reinforcer Points Earned
timeFrame: Baseline
measure: Phase 1: Baseline Delay Discounting (Computer Task), Area Under the Curve Representing the Ratio of Immediate Reward Size to Time Delay
timeFrame: Baseline
measure: Phase 1: Baseline Implicit Wanting, Reaction Time on Leeds Food Preference Questionnaire
timeFrame: Baseline
measure: Phase 1: Baseline Fasting Ghrelin
timeFrame: Baseline
measure: Phase 1: Baseline Fasting Leptin
timeFrame: Baseline
measure: Phase 1: Baseline Postprandial Change in Insulin During a Test Meal
timeFrame: Baseline
measure: Phase 1: Baseline Postprandial Change in Peptide YY During a Test Meal
timeFrame: Baseline
measure: Phase 2: Weight Loss (kg)
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Number of Participants With a Weight Loss of 5% or Greater of Randomization Body Weight at Week 24
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Number of Participants With a Weight Loss of 10% or Greater of Randomization Body Weight at Week 24
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Appetite Suppression, as Measured by Visual Analogue Scales (Range 0-100 mm) During a Test Meal
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Hunger, as Measured by Visual Analogue Scales (Range 0-100 mm, Higher=More Hunger) During a Test Meal
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Delay Discounting (Computer Task), Area Under the Curve Representing the Ratio of Immediate Reward Size to Time Delay
timeFrame: Week 0 (randomization) to week 24
Other outcomes:
measure: 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)
timeFrame: Baseline
measure: 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)
timeFrame: Baseline
measure: Phase 1: Baseline Reinforcing Value of Food as Measured by the Power of Food Scale
timeFrame: Baseline
measure: Phase 1: Baseline Sensitivity to Reward as Measured by the Behavioral Inhibition/Activation Scale (BIS/BAS)
timeFrame: Baseline
measure: Phase 1: Baseline Impulsivity as Measured by The Barratt Impulsiveness Scale
timeFrame: Baseline
measure: 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
timeFrame: Baseline
measure: Phase 1: Baseline Craving Frequency as Measured by the Food Craving Q Trait - Reduced
timeFrame: Baseline
measure: Phase 1: Baseline Emotional Eating as Measured by the Dutch Eating Behaviour Questionnaire (DEBQ)
timeFrame: Baseline
measure: Phase 1: Baseline Perceived Barriers to Healthy Eating and Physical Activity (Scale by Welsh et al., 2012)
timeFrame: Baseline
measure: Phase 1: Baseline Weight Efficacy Life-Style Questionnaire (WEL)
timeFrame: Baseline
measure: Phase 1: Baseline SCI Exercise Self Efficacy Scale (ESES)
timeFrame: Baseline
measure: Phase 1: Randomization Ball and Crawford Social Support Scale
timeFrame: Randomization (week 0)
measure: Phase 1: Baseline Food Addiction Using the Yale Food Addiction Scale (YFAS)
timeFrame: Baseline
measure: Phase 1: The Reinforcing Efficacy of High- and Low-calorie Food
timeFrame: Baseline
measure: Phase 1: Baseline Sleep Hours Survey
timeFrame: Baseline
measure: Phase 1: Baseline Perceived Stress Scale
timeFrame: Baseline
measure: Phase 1: Baseline Anxiety as Measured by the GAD-7
timeFrame: Baseline
measure: Phase 1: Baseline General Mindfulness and Acceptance as Measured Using the Philadelphia Mindfulness Scale
timeFrame: Baseline
measure: Phase 2: Change in Blood Pressure (Systolic)
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Pulse
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Triglycerides
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in HDL and LDL Cholesterol
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Fasting Blood Sugar
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Appetite Ratings (Ratings of Appetite During the Past Week Using Visual Analogue Scales, Scored 0-100 mm)
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Weight-related Quality of Life as Measured by the Impact of Weight on Quality of Life (IWQOL)
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Depressive Symptoms as Measured by the Patient Health Questionnaire (PHQ-9)
timeFrame: Week 0 (randomization) to week 24
measure: Phase 2: Change in Physical Activity Using the Paffenbarger Physical Activity Questionnaire
timeFrame: Week 0 (randomization) to week 24
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania Center for Weight and Eating Disorders
state: Pennsylvania
Study officials:
affiliation: Perelman School of Medicine at the University of Pennsylvania
name: Jena S Tronieri, PhD
role: PRINCIPAL_INVESTIGATOR
References: