Topiramate in Adolescents With Severe Obesity

Study Overview
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Brief Summary
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The prevalence of severe pediatric obesity is on the rise and youth with this condition are at elevated risk for developing chronic diseases such as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Topiramate, a medication approved by the Food and Drug Administration (FDA) for the treatment of seizures in adults and children, is associated with weight loss. Although not FDA approved for the treatment of obesity, studies in obese adults have demonstrated weight reduction of approximately 5% with 6-12 months of therapy. However, the weight loss effect of topiramate has never been evaluated among children and adolescents. Therefore, the goal of this pilot study is to evaluate the safety and efficacy of 24 weeks of topiramate therapy with a 4-week run-in of meal replacement therapy in adolescents with severe obesity. The primary hypothesis is that 4 weeks of meal replacement therapy followed by 24 weeks of topiramate will have a larger average percent decline in BMI between baseline and 28 weeks compared to meal replacement therapy followed by placebo.

Detailed Description
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The prevalence of severe pediatric obesity is on the rise and youth with this condition are at elevated risk for developing chronic diseases such as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Lifestyle modification therapy alone is ineffective for most adolescents with severe obesity and few patients qualify for bariatric surgery. Many patients would likely benefit from pharmacotherapy but only one medication (orlistat) is approved for use in adolescents but notable side effects and limited efficacy impede its clinical use. Topiramate, a medication approved by the Food and Drug Administration (FDA) for the treatment of seizures in adults and children, is associated with weight loss. Although not FDA approved for the treatment of obesity, studies in obese adults have demonstrated weight reduction of approximately 5% with 6-12 months of therapy. However, the weight loss effect of topiramate has never been evaluated among children and adolescents. Therefore, the goal of this pilot study is to evaluate the safety and efficacy of 24 weeks of topiramate therapy with a 4-week run-in of meal replacement therapy in adolescents with severe obesity. This will be a 28-week, randomized, double-blind, placebo-controlled, pilot clinical trial of meal replacement therapy (4 weeks) followed by topiramate (24 weeks) vs. meal replacement therapy (4 weeks) followed by placebo (24 weeks) for BMI reduction and cardiometabolic risk factor improvement in 36 adolescents (ages 12-17 years old) with severe obesity. Monthly lifestyle modification/behavioral counseling will be delivered by trained study coordinators to patients in both groups. The lifestyle modification education materials will be given to patients and selected sections will be discussed at each monthly contact (five face-to-face sessions and three phone sessions).

Official Title
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BMI Reduction With Meal Replacements + Topiramate in Adolescents With Severe Obesity

Conditions
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Obesity, Morbid, Obesity, Weight Loss

Intervention / Treatment
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* Drug: Topiramate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥1.2 times the 95th percentile (based on gender and age) or BMI ≥35 kg/m2 12-18 years old Tanner stage IV or V by physical exam Exclusion Criteria: Tanner stage I, II, or III Type 1 or 2 diabetes mellitus Previous (within 6-months) or current use of weight loss medication (patients may undergo washout) Previous (within 6-months) or current use of drugs associated with weight gain (e.g. steroids/anti-psychotics) Previous bariatric surgery Recent initiation (within 3-months) of anti-hypertensive or lipid medication Previous (within 6-months) or current use of medication to treat insulin resistance or hyperglycemia (patients may undergo washout) Major psychiatric disorder Females: 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 >2.5 times the upper limit of normal Bicarbonate <18 mmol/L Creatinine >1.2 mg/dL Glaucoma Obesity associated with genetic disorder (monogenetic obesity) Hyperthyroidism or uncontrolled hypothyroidism History of suicidal thought/attempts History of kidney stones History of cholelithiasis Current use of other carbonic anhydrase inhibitor

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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No

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate<br>Four (4) weeks of meal replacement therapy, followed by 28-weeks of topiramate therapy. Topiramate will be initiated at a dose of 25 mg (taken orally once daily in the evening), escalated to 50 mg (taken orally once daily in the evening) after 1 week, and escalated to 75 mg (taken orally 25 mg in the morning and 50 mg in the evening) after 2 weeks. | Drug: Topiramate<br>* Topiramate will be initiated at a dose of 25 mg (taken orally once daily in the evening), escalated to 50 mg (taken orally once daily in the evening) after 1 week, and escalated to 75 mg (taken orally 25 mg in the morning and 50 mg in the evening) after 2 weeks. Patients who do not tolerate dose escalation will be reduced to the highest tolerated dose for the remainder of the trial.<br>* Other names: Topamax;|
| Placebo Comparator: Sugar Pill<br>Four (4) weeks of meal replacement therapy, followed by 28-weeks of placebo (sugar pill) therapy. | Other: Placebo<br>* Placebo will be taken orally once daily in the evening for the first two weeks, and orally twice daily (AM and PM) for the remainder of the study.<br>* Other names: Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Body Mass Index at 28-Weeks | The Percent Change from Baseline in Body Mass Index at 28-Weeks | Baseline and 28-Weeks |