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Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in Youth: PHARMATOP (PHARMATOP)

Primary Purpose

Obesity, Childhood

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Topiramate Tablets

About this trial

This is an interventional treatment trial for Obesity, Childhood

Eligibility Criteria

12 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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 glaucoma
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 stimulant medications, unless participant has been on stable doses of such medication for ≥ 6 months. Of note, in cases where a participant takes a short-acting dose of an ADHD stimulant medication in the afternoon only during school/work days, 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

Sites / Locations

University of MinnesotaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Topiramate

Arm Description

Individuals will receive 75 mg of topiramate daily. The dose will start at 25 mg daily for the first week. The second week participants will receive 50 mg daily. Starting at week 3 participants will take 75 mg daily.

Outcomes

Primary Outcome Measures

To determine associations between topiramate exposure and 3-month BMI change using pharmacodynamic modeling

Change in body mass index (BMI) as assessed by percent change in BMI from baseline to Month 3

Secondary Outcome Measures

Full Information

NCT ID

NCT04986631

First Posted

July 16, 2021

Last Updated

October 16, 2023

Sponsor

University of Minnesota

1. Study Identification

Unique Protocol Identification Number

NCT04986631

Brief Title

Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in Youth: PHARMATOP

Acronym

PHARMATOP

Official Title

Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in Youth: PHARMATOP

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 4, 2022 (Actual)

Primary Completion Date

November 2024 (Anticipated)

Study Completion Date

November 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obesity, Childhood

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

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.

Masking

None (Open Label)

Allocation

N/A

Enrollment

65 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Topiramate

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Topiramate Tablets

Intervention Description

Topiramate intervention

Primary Outcome Measure Information:

Title

To determine associations between topiramate exposure and 3-month BMI change using pharmacodynamic modeling

Description

Change in body mass index (BMI) as assessed by percent change in BMI from baseline to Month 3

Time Frame

3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 glaucoma 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 stimulant medications, unless participant has been on stable doses of such medication for ≥ 6 months. Of note, in cases where a participant takes a short-acting dose of an ADHD stimulant medication in the afternoon only during school/work days, 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Eric Bomberg, MD

Phone

(612) 301-2563

bombe002@umn.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Eric Bomberg, MD

Organizational Affiliation

University of Minnesota

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Eric Bomberg

Phone

612-301-2563

bombe002@umn.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Summary data that has been de-identified will be made available to other researchers

Learn more about this trial

Pharmacokinetics and Pharmacodynamics of Topiramate for Weight Loss in Youth: PHARMATOP

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