Enhancing Weight Loss Maintenance With GLP-1RA (BYDUREON™) in Adolescents With Severe Obesity

Study Overview
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Brief Summary
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Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations involving appetite, satiety, and energy expenditure in the post- weight loss setting. Following a loss in body weight, peripheral and central mechanisms convey a sense that energy reserves have dwindled, activating a strong counter response to increase caloric intake. Adolescents with severe obesity are not immune to the vexing issue of weight regain. Indeed, only 2% are able to achieve and maintain clinically-meaningful weight loss with lifestyle modification therapy. Therefore, novel treatment paradigms focused on long-term weight loss maintenance are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting specific counter-regulatory mechanisms in the post- weight loss setting. One of the most promising candidates is the glucagon like peptide-1 receptor agonist (GLP-1RA) class, which greatly enhanced weight loss maintenance following a short-term low calorie diet among adults with obesity. The rationale for focusing on GLP-1RA treatment (BYDUREON™) to prevent weight regain is supported by the multiple central and peripheral mechanisms of action targeted by this class of drug; many of which specifically address the biological adaptations known to induce relapse. The investigators have strong preliminary data demonstrating that GLP-1RA treatment reduces BMI in adolescents with severe obesity. Moreover, the investigators and others have shown that although meal replacement therapy (structured meals of known caloric content) can elicit robust short-term weight loss among adolescents with severe obesity, weight regain is a pervasive problem. Therefore, in this clinical trial, our innovative approach will utilize GLP-1RA treatment to target weight regain following short-term meal replacement therapy in youth with severe obesity. Participants who achieve ≥5% BMI reduction during the meal replacement phase will be randomized to GLP-1RA treatment or placebo for an additional 52 weeks while simultaneously engaging in lifestyle modification therapy. Importantly, this study will also allow us to examine the extent to which GLP-1RA treatment addresses mechanisms of weight regain, investigate other pleiotropic benefits of GLP-1RA, and identify predictors of weight loss response.

Detailed Description
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Primary Objective Evaluate the effect of GLP-1RA treatment on the maintenance of weight loss and durability of cardiometabolic risk factor improvements among adolescents with severe obesity following a meal replacement induction period. The investigators hypothesize that adolescents with severe obesity receiving GLP-1RA treatment following a short-term meal replacement induction period will demonstrate superior maintenance of initial BMI reduction 52 weeks following randomization compared to those assigned to placebo (primary endpoint) and that a higher proportion of those assigned to GLP-1RA treatment vs. placebo will maintain ≥5% BMI reduction from baseline to the 52-week time point (secondary endpoint).

Official Title
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Enhancing Weight Loss Maintenance With GLP-1RA (BYDUREON™) in Adolescents With Severe Obesity

Conditions
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Severe Obesity

Intervention / Treatment
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* Drug: Weight loss with pharmacotherapy
* Drug: Weight loss without pharmacotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥1.2 times the 95th percentile (based on sex and age) or BMI ≥35 kg/m2 12-17 years old Exclusion Criteria: Type 1 or 2 diabetes mellitus Previous (within 6 months) or current use of medication(s) prescribed primarily for weight loss (refer to appendix material for comprehensive list) If currently using weight altering drug(s) for non-obesity indication(s) (refer to appendix material for comprehensive list), any change in drug(s) or dose within the previous 6 months Previous bariatric surgery If currently using anti-hypertensive medication(s), lipid medication(s), and/or medication(s) to treat insulin resistance (refer to appendix material for comprehensive list), any change in drug(s) or dose within the previous 6 months If currently using CPAP/BIPAP (for sleep apnea), change in frequency of use or settings within the previous 6 months History of treatment with growth hormone Neurodevelopmental disorder severe enough to impair ability to comply with study protocol Clinical diagnosis of bipolar illness, schizophrenia, conduct disorder, and/or substance use/abuse Females: currently pregnant, planning to become pregnant, or unwilling to use 2 or more acceptable methods of contraception when engaging in sexual activity throughout the study Tobacco use Liver/renal dysfunction ALT or AST >2 times the upper limit of normal Bicarbonate <18 mmol/L Creatinine >1.2 mg/dL History of pancreatitis Personal- and/or family history of medullary thyroid carcinoma Personal- and/or family history of multiple endocrine neoplasia type 2 Calcitonin level >50 ng/L Bulimia nervosa Neurological disorder Hypothalamic obesity Obesity associated with genetic disorder (monogenetic obesity) Hyperthyroidism or uncontrolled hypothyroidism History of suicide attempt History of suicidal ideation or self-harm within the past year History of cholelithiasis

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Individuals who consented to the project were enrolled in a screening phase of the study where they received meal replacement therapy in attempt to achieve a >/= 5% body mass reduction. Individuals who did not meet this goal were considered screen failures. Individuals who met this goal were allowed to remain in the study and be randomized to one of the treatment arms (placebo or GLP-1 RA). A total of 100 participants consented and were enrolled and 66 participants achieved the required BMI reduction with MRT and were randomized to study treatment (33 to GLP-1 RA (exenatide) and 33 to placebo).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Weight Loss Maintenance without Pharmacotherapy<br>Individuals who, after a short-term (1-3 month) meal replacement induction period, achieve ≥5% BMI reduction. A selection of these participants are then randomized to receive treatment with placebo. | Drug: Weight loss without pharmacotherapy<br>* Participants randomized to the placebo group will receive a placebo.<br>* Other names: Placebo;|
| Active Comparator: Weight Loss Maintenance with Pharmacotherapy<br>Individuals who, after a short-term (1-3 month) meal replacement induction period, achieve a >/= 5% BMI reduction. A selection of these participants are then randomized to receive treatment with GLP-1RA. | Drug: Weight loss with pharmacotherapy<br>* Participants randomized to the drug intervention group will receive Exenatide extended-release.<br>* Other names: Exenatide extended release;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Mass Index | Percentage of body mass index change from Randomization to Week 52 | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exenatide, BYDUREON, Weight Loss, Maintenance, Pharmacotherapy, Children, Obesity, GLP-1