Role of Pharmacotherapy in Counteracting Weight Regain in Adolescents With Severe Obesity

NCT04298203 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: PEDS-2020-28498
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations occurring in the post-weight loss setting, including neuroendocrine-mediated changes in appetite/satiety and reduction of energy expenditure. Following weight loss, peripheral and central mechanisms respond in a way similar to starvation by conveying a sense that energy reserves have dwindled, activating a strong counter-response to increase caloric intake. Moreover, metabolic rate drops, further compounding the propensity for weight rebound. Adolescents with severe obesity are not immune to the vexing issue of weight regain; therefore, effective and scalable treatments are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting counter-regulatory mechanisms in the post-weight loss setting. Unfortunately, only one obesity medication is FDA-approved for long-term use in adolescents and is seldom prescribed owing to modest efficacy and notable side effects. Among the most promising candidates in the pediatric pipeline is the combination of phentermine and topiramate, which is the most effective adult weight loss medication currently available. The mechanisms of action are thought to reduce appetite, enhance satiety, and potentially increase energy expenditure, making this medication particularly well-suited for the purpose of weight loss maintenance since it targets many of the biological adaptations known to induce relapse and subsequent weight regain. The investigators have generated preliminary data demonstrating that both phentermine and topiramate reduce BMI in adolescents with severe obesity and have acceptable safety profiles. In this clinical trial, the investigators will utilize combination phentermine/topiramate to target counter-regulatory pathways responsible for weight regain after meal replacement therapy (structured meals of known caloric content) in adolescents with severe obesity with a goal of enhancing weight loss maintenance and improving obesity-related complications. Importantly, the investigators will maximize the clinical utility and overall impact of the study by comprehensively characterizing the safety of phentermine/topiramate utilizing sensitive measures of cardiac autonomic function, arterial stiffness, cognition, and bone health as well as examine the extent to which this medication counteracts mechanisms of weight regain.

Conditions

Obesity

Keywords

Childhood; Adolescent

Outcome Measures

Primary Outcomes (9)

• To measure changes in BMI.

  The investigators will measure the change in BMI reduction during the meal replacement therapy intervention as well as during the treatment with phentermine/topiramate or placebo. Weight and height will be combined to report BMI in kg/m\^2

  58 weeks.

• To measure changes in total body fat

  The investigators will measure the change in total body fat during the meal replacement therapy intervention and during the treatment with phentermine/topiramate or placebo via use of dual-energy x-ray absorptiometry (iDXA).

  iDXA will be conducted at four timepoints (Baseline, 1 day of Randomization, Week 26 and Week 52).

• To measure changes in visceral fat.

  The investigators will measure the change in visceral fat during the meal replacement therapy intervention and during the treatment with phentermine/topiramate or placebo via use of the iDXA.

  iDXA will be conducted at four timepoints (Baseline, 1 day of Randomization, Week 26 and Week 52).

• To measure changes in lipids.

  Lipids (consisting of total lipids, LDL, HDL, cholesterol and triglycerides)

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

• To measure changes in glucose.

  The investigators will track whether fasting glucose levels come down during the course of participation in the study. Glucose can be an indicator of diabetes. Typical fasting glucose ranges for individuals 6 months and older are approximately 70-99 mg/dL. Investigators will track whether glucose levels reduce during the course of the study.

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

• To measure changes in insulin.

  Investigators will track whether insulin levels reduce during the course of the study.

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

• To measure changes in hemoglobin A1c.

  Investigators will track whether hemoglobin A1c levels (which can indicate pre-diabetes or diabetes) decrease during the course of the study. Normal ranges for hemoglobin A1c are less than 5/7%. Prediabetes ranges are 5.7-7.5% and diabetes ranges are 6.5% or greater.

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

• To measure changes in C-reactive protein (CRP).

  C-reactive protein tests help to measure cardiac risk. Investigators will review C-reactive protein levels during the study to see if they decrease. Normal ranges for CRP are: \<1 mg/L for low risk, 1.0-3.0 mg/L for average risk, \>3.0 mg/L for high risk and \> 10.0 mg/L for acute inflammation.

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

• To measure changes in oxidized LDL.

  Investigators will measure changes in oxidized low-density lipoprotein. Oxidized LDL is a potentially harmful cholesterol that is produced in the body when normal LDL cholesterol is damaged by chemical interactions.

  Baseline, 1 day of Randomization, Week 26 and Week 52 visits.

Study Arms (3)

Meal Replacement Therapy

EXPERIMENTAL

Participants who are enrolled in the study will be administered a short-term (six weeks) meal replacement induction period. Because the trial is deigned to evaluate weight loss maintenance, participants must achieve at least 5% BMI reduction at week six of the meal replacement period in order to be randomized. Subjects will be asked to strictly follow the eating regimen, which will include a total of approximately 1,000 kcals per day of commercially-available liquid shakes (breakfast and lunch), pre-packaged frozen entrée meals for dinner, two servings of fruit, and three servings of vegetables. Shakes/meals will be provided free of charge - fruits/vegetables will be purchased by the participants. Guidance will be provided regarding the use of the meal replacement shakes at school, and participants will be encouraged to engage in family meal sessions despite eating different foods.

Dietary Supplement: Meal Replacement Therapy

Phentermine/Topiramate

ACTIVE COMPARATOR

Participants who achieve at least 5% BMI reduction at week six of the meal replacement period will be randomized (1:1) to receive either phentermine/topiramate or placebo. Participants randomized to phentermine/topiramate will start treatment at 3.75 mg/23 mg orally once daily in the morning for 14 days, then increased to 7.5 mg/46 mg orally once daily in the morning for 14 days, then be increased to 11.25 mg/69 mg orally once daily in the morning for 14 days, then increased to 15 mg/92 mg orally once daily in the morning for the remainder of the trial. Following the final study visit, participants will be down-titrated gradually by taking medication every other day for seven days before stopping treatment altogether.

Drug: Phentermine-Topiramate; Other: Placebo

Placebo

PLACEBO COMPARATOR

Participants who achieve at least 5% BMI reduction at week six of the meal replacement period will be randomized (1:1) to receive either phentermine/topiramate or placebo. Participants randomized to the placebo will receive inert tablets that look like the active comparator. In order to mimic the active comparator arm, subjects randomized to the placebo arm will up titrate their placebo at the beginning of the study treatment and will down titrate as in the active comparator arm. Participants will be instructed to take the medication under the supervision of a parent/guardian and pill counts of returned product will serve as a proxy of treatment compliance.

Drug: Phentermine-Topiramate; Other: Placebo

Interventions

Phentermine-Topiramate DRUG

The study medication to be tested for this study is a combination of phentermine and topiramate.

Also known as: Qsymia

Phentermine/Topiramate; Placebo

Meal Replacement Therapy DIETARY_SUPPLEMENT

The first six weeks of the study, subjects will receive meal replacement therapy in an effort to reduce their BMI by at least 5%.

Meal Replacement Therapy

Placebo OTHER

A pill that looks like Phentermine-Topiramate but has no active medication.

Phentermine/Topiramate; Placebo

Eligibility Criteria

• Age: 12 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Severe obesity (BMI \>/= 120% of the 95th percentile or BMI \>/= 35 kg/m2)
• Age 12 to \< 18 years of age at enrollment (screening) and Tanner stage \>/= 2 - Female participants who are sexually active with males and who are able to get pregnant must agree to use two forms of contraception throughout the trial

You may not qualify if:

• Diabetes (type 1 or 2)
• Previous metabolic/bariatric surgery
• Current use of a stimulant medication
• History of glaucoma
• Current or recent (\<14 days) use of monoamine oxidase inhibitor
• Known hypersensitivity to sympathomimetic amines
• Any history of treatment with growth hormone
• Any history of bulimia nervosa
• Major psychiatric disorder as determined by the local medical monitor
• Unstable and clinically-diagnosed (defined as documented in the medical record, if available) depression
• Any history of active suicide attempt
• History of suicidal ideation or self-harm within the previous 30 days of screening
• Patient Health Questionnaire (PHQ-9) score \>15 at screening
• Current pregnancy or plans to become pregnant during study participation
• Current tobacco use

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Obesity

Interventions

Qsymia

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Aaron Kelly, PhD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, care providers, study investigators and the study team will be blinded to the phentermine/topiramate or placebo assignment.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants, regardless of drug/placebo assignment, will receive the same lifestyle/behavioral modification counseling monthly throughout the study: delivered at each in-person study visit and on the phone for months when there is no study visit. All participants will engage in a meal replacement induction period for six weeks with a goal of reducing individual BMI by at least 5%. Those who are successful will be randomized to the study treatment outlined below. Those who are not successful will be discontinued from the study at this point. Participants will be randomized (1:1) to phentermine/topiramate or placebo immediately following the meal replacement induction period (if successful in achieving \>/= 5% BMI reduction within the allotted six weeks).

Study Record Dates

• First Submitted: February 21, 2020
• First Posted: March 6, 2020
• Study Start: August 4, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2027
• Last Updated: April 8, 2026

Record last verified: 2026-04

Locations

US (1)