Topiramate in Adolescents With Severe Obesity

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).

The primary object is to evaluate the effect of meal replacement therapy followed by
topiramate vs. meal replacement therapy followed by placebo on percent change in BMI among
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.

The secondary objective is to characterize the safety profile of topiramate for the
treatment of adolescent obesity, evaluate the effects of meal replacement therapy followed
by topiramate vs. meal replacement therapy followed by placebo on risk factors for CVD and
T2DM, and evaluate response to topiramate treatment based on baseline eating behavior
phenotype in adolescents with severe obesity. The secondary hypothesis is that 4 weeks of
meal replacement therapy followed by 24 weeks of topiramate will significantly reduce
average absolute BMI, absolute and percent body weight, percent total body and visceral fat,
systolic blood pressure, fasting triglycerides and insulin, compared to meal replacement
therapy followed by placebo, and that the presence of binge eating disorder characteristics
at baseline will be associated with greater reduction in BMI with topiramate treatment.

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