Obesity, Childhood
Conditions
Brief summary
Pediatric severe obesity is the fastest growing obesity category in the United States, and anti-obesity pharmacotherapies are promising adjuncts to lifestyle modification (LSM) for the treatment of this disease. While anti-obesity pharmacotherapies have overall been associated with mean weight loss, there is substantial variability in their individual-level effectiveness. While some patients lose a significant amount of weight with anti-obesity pharmacotherapies, others lose little or even gain weight. Due to this well-recognized variability in individual-level response, the National Institutes of Health (NIH) has recognized the importance of using precision medicine approaches in order to optimize treatments for pediatric severe obesity. Pharmacometrics, which uses mathematical models to study medication dose-exposure (i.e. blood drug concentrations)-response relationships, is an emerging science that can help determine optimal dosing regimens based upon patient-specific characteristics. Pharmacometrics quantitates the interplay between pharmacokinetics (PK; drug dose-exposure associations) and pharmacodynamics (PD; drug exposure-response associations). Population PK (popPK), a type of PK, can be used to quantitate variability in drug exposure among individuals in order to help inform recommendations on therapeutic individualization (e.g. through tailored dosing). In this study, investigators will use popPK/PD modeling to characterize associations between anti-obesity pharmacotherapy dose, exposure, and changes in weight and weight-related outcomes in youth with severe obesity. This study will focus on topiramate because this medication is commonly prescribed for weight loss in youth with severe obesity and has been associated with highly variable individual-level effectiveness.
Detailed description
The weight loss achieved with topiramate occurs through several purported mechanisms including reductions in appetite, food cravings, and binge eating, and adverse alterations in taste for carbonated beverages. It is hypothesized that some of the individual-level effectiveness of this medication on weight loss response is secondary to patient-specific differences in these factors. In a 3.5-month pragmatic-based prospective cohort study (n=65), the investigators will develop a popPK model using sparse sampling by drawing a series of topiramate concentration measures over time in order to begin determining patient-specific factors that contribute to topiramate exposure variability. The investigators will also identity associations between topiramate exposure, changes in eating behaviors, and weight loss outcomes through PD models using regression techniques. It is hypothesized that patient-specific characteristics (i.e. age, body mass index (BMI), and sex) will explain some variability in topiramate exposure in youth, and that higher topiramate exposure will be associated with greater improvements in weight loss response and eating behaviors among youth prescribed this medicine for the treatment of pediatric severe obesity.
Interventions
Topiramate intervention
Sponsors
University of Minnesota
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Individuals in this pilot study will be 12-\<18 years of age at enrollment. All participants will receive topiramate for 3.5 months.
Eligibility
Sex/Gender
ALL
Age
12 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) \</= 1.2 times the 95th percentile (age and sex-adjusted) and/or BMI \>/= 35 kg/m2 * Ages 12 to \< 18 years old * Deemed appropriate candidates to receive topiramate (without contraindications) for weight loss by an obesity medicine specialist at the University of Minnesota
Exclusion criteria
* History of metabolic/bariatric surgery * Obesity associated with a diagnosed genetic disorder (i.e. monogenic obesity, Prader-Willi, Bardet-Biedl syndrome) * Clinically diagnosed hyperthyroidism or uncontrolled hypothyroidism as determined by local medical monitor (who is a board certified endocrinologist) * History of acute angle closure glaucoma. Individuals with other types of glaucoma will need approval from the participant's ophthalmologist to be enrolled. * History of nephrolithiasis * History of seizures (aside from febrile seizures) * Major psychiatric disorder as determined by local medical monitor * History of bulimia nervosa or anorexia nervosa * History of suicide attempt within the last year \* History of active suicidal ideation or self-harm within the past 30 days * Current or recent (\< 6 months prior to enrollment) use of anti-obesity medication(s) defined as orlistat, phentermine, topiramate, combination phentermine/topiramate, liraglutide (or other glucagon-like peptide (GLP1-RA)), and/or combination naltrexone/bupropion (monotherapy use of naltrexone or bupropion is not an exclusion), unless participant has been on stable doses for \>/= 6 months. Of note, if phentermine was increased from 15 mg daily to 18.75 mg daily during this period, it is not considered a dose increase. * Current or recent (\< 6 months prior to enrollment) use of medication(s) associated with weight gain (e.g. oral steroids, anti-psychotics), unless participant has been on stable doses of such medication(s) for ≥ 6 months * Current or recent (\< 6 months prior to enrollment) use of long-acting stimulant medications, unless participant has been on stable doses of such medication for ≥ 6 months. In terms of short-acting ADHD stimulant medications, the PI will determine eligibility based on weight and dose (no studies have shown this contributes to weight outcomes) * Baseline bicarbonate \< 18 mmol/L * Baseline creatinine \> 1.2 mg/dL * Females: pregnant, planning to become pregnant, or, if sexually active, unwilling to use 2+ acceptable contraceptive methods during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent BMI Change | 14 Weeks | Percent change in body mass index (BMI) from baseline to 14 weeks (mean change from baseline to 14 weeks of follow up, analysis using paired t-tests) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREric Bomberg, MD
University of Minnesota
Participant flow
Recruitment details
Participants were recruited directly from our pediatric weight management clinics by providers within the clinic. Participants were also recruited using IRB approved mailers and social media.
Pre-assignment details
This was an open-label study in which all participants received topiramate (tablets) plus two health behavior and lifestyle intervention sessions throughout the study duration. For all participants, topiramate dose was titrated up by 25 mg increments to 75 mg daily (or maximum tolerated dose, i.e. 25 mg daily for week 1, 50 mg for week 2, and 75 mg daily for weeks 3-14).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 65 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants |
| Race/Ethnicity, Customized Black | 4 Participants |
| Race/Ethnicity, Customized More than One Race | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White | 47 Participants |
| Region of Enrollment United States | 65 participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 65 |
| other Total, other adverse events | 51 / 65 |
| serious Total, serious adverse events | 0 / 65 |
Outcome results
None listed