Obesity, Obesity, Morbid, Weight Loss
Conditions
Brief summary
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
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).
Interventions
DRUGTopiramate
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.
OTHERPlacebo
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.
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Body Mass Index at 28-Weeks | Baseline and 28-Weeks | The Percent Change from Baseline in Body Mass Index at 28-Weeks |
Countries
United States
Participant flow
Pre-assignment details
34 subjects enrolled and 30 were started on the study medication or placebo
Participants by arm
| Arm | Count |
|---|---|
| Topiramate 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.
Topiramate: 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. | 16 |
| Sugar Pill Four (4) weeks of meal replacement therapy, followed by 28-weeks of placebo (sugar pill) therapy.
Placebo: 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. | 14 |
| Total | 30 |
Baseline characteristics
| Characteristic | Sugar Pill | Topiramate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 14 Participants | 16 Participants | 30 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 15.7 years STANDARD_DEVIATION 1.8 | 14.9 years STANDARD_DEVIATION 1.6 | 15.2 years STANDARD_DEVIATION 1.7 |
| Region of Enrollment United States | 14 participants | 16 participants | 30 participants |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 14 |
Outcome results
Primary
Percent Change From Baseline in Body Mass Index at 28-Weeks
The Percent Change from Baseline in Body Mass Index at 28-Weeks
Time frame: Baseline and 28-Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate | Percent Change From Baseline in Body Mass Index at 28-Weeks | -2.74 % change BMI | Standard Deviation 3.74 |
| Sugar Pill | Percent Change From Baseline in Body Mass Index at 28-Weeks | -0.85 % change BMI | Standard Deviation 5.31 |