Severe Obesity
Conditions
Keywords
Obesity, Pharmacotherapy, GLP-1, Children, Exenatide, BYDUREON, Weight Loss, Maintenance
Brief summary
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
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).
Interventions
Participants randomized to the drug intervention group will receive Exenatide extended-release.
Participants randomized to the placebo group will receive a placebo.
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body Mass Index | 52 weeks | Percentage of body mass index change from Randomization to Week 52 |
Countries
United States
Participant flow
Recruitment details
100 participants consented to enroll in the study and entered the screening phase. During the screening phase participants entered and 8-week meal replacement therapy phase to help them meet a goal of achieving reducing their body mass by 5% or more. Only those participants who met this weight loss goal passed the study screening and were allowed to be randomized to receive placebo or GLP-1 RA. 66 participants met the BMI weight loss goal, 34 participants did not pass the screening phase.
Pre-assignment details
Only individuals who achieve the \>/= 5% BMI reduction will be considered to have passed screening and will be allowed to be randomized to treatment with GLP-1 RA or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Weight Loss Maintenance Without Pharmacotherapy A short-term (1-3 month) meal replacement induction period design to achieve ≥5% BMI reduction. If participants achieve ≥5% BMI they will be randomized to drug or placebo in phase 2 of the trail.
Meal Replacement Therapy: A short-term meal replacement induction period designed to achieve \>5% BMI reduction in 1, 2, or 3 months. | 33 |
| Weight Loss Maintenance With Pharmacotherapy We 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)
Exenatide extended-release for injectable suspension (BYDUREON™) | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Weight Loss Maintenance Without Pharmacotherapy | Weight Loss Maintenance With Pharmacotherapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 33 Participants | 33 Participants | 66 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 27 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 13 Participants | 18 Participants | 31 Participants |
| Sex: Female, Male Male | 20 Participants | 15 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 33 | 0 / 100 |
| other Total, other adverse events | 30 / 33 | 32 / 33 | 0 / 100 |
| serious Total, serious adverse events | 0 / 33 | 1 / 33 | 0 / 100 |
Outcome results
Primary
Body Mass Index
Percentage of body mass index change from Randomization to Week 52
Time frame: 52 weeks
Population: Change in body mass index (percentage) from Randomization to Week 52.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Weight Loss Maintenance Without Pharmacotherapy | Body Mass Index | 10.1 percentage (body mass index) | Standard Deviation 9 |
| Weight Loss Maintenance With Pharmacotherapy | Body Mass Index | 4.6 percentage (body mass index) | Standard Deviation 10.5 |