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

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ClinicalTrials.gov Identifier: NCT04298203
Recruitment Status : Recruiting
First Posted : March 6, 2020
Last Update Posted : October 26, 2021
Sponsor:
Information provided by (Responsible Party):
University of Minnesota

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.

Condition or disease Intervention/treatment Phase
Obesity Drug: Phentermine-Topiramate Dietary Supplement: Meal Replacement Therapy Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 143 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

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).

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Participants, care providers, study investigators and the study team will be blinded to the phentermine/topiramate or placebo assignment.
Primary Purpose: Treatment
Official Title: Role of Pharmacotherapy in Counteracting Weight Regain in Adolescents With Severe Obesity
Actual Study Start Date : August 4, 2021
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : June 30, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Body Weight

Arm Intervention/treatment
Experimental: Meal Replacement Therapy
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
The first six weeks of the study, subjects will receive meal replacement therapy in an effort to reduce their BMI by at least 5%.

Active Comparator: Phentermine/Topiramate
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
The study medication to be tested for this study is a combination of phentermine and topiramate.
Other Name: Qsymia

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

Placebo Comparator: Placebo
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
The study medication to be tested for this study is a combination of phentermine and topiramate.
Other Name: Qsymia

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




Primary Outcome Measures :
  1. To measure changes in BMI. [ Time Frame: 58 weeks. ]
    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

  2. To measure changes in total body fat [ Time Frame: iDXA will be conducted at four timepoints (Baseline, 1 day of Randomization, Week 26 and Week 52). ]
    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).

  3. To measure changes in visceral fat. [ Time Frame: iDXA will be conducted at four timepoints (Baseline, 1 day of Randomization, Week 26 and Week 52). ]
    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.

  4. To measure changes in arterial stiffness. [ Time Frame: SphygmoCor testing will be conducted at four timepoints (Baseline, 1 day of Randomization, Week 26 and Week 52). ]
    The investigators will measure the change in arterial stiffness during the meal replacement therapy intervention and during the treatment with phentermine/topiramate or placebo via SphygmoCor testing.

  5. To measure changes in lipids. [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    Lipids (consisting of total lipids, LDL, HDL, cholesterol and triglycerides)

  6. To measure changes in glucose. [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    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.

  7. To measure changes in insulin. [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    Investigators will track whether insulin levels reduce during the course of the study.

  8. To measure changes in hemoglobin A1c. [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    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.

  9. To measure changes in C-reactive protein (CRP). [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    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.

  10. To measure changes in oxidized LDL. [ Time Frame: Baseline, 1 day of Randomization, Week 26 and Week 52 visits. ]
    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.



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Ages Eligible for Study:   12 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • Diabetes (type 1 or 2)
  • Current or recent (< six months prior to enrollment) use of anti-obesity medication(s) defined as orlistat, phentermine, topiramate, combination phentermine/topiramate, liraglutide, and/or combination naltrexone/bupropion (monotherapy use of naltrexone or bupropion is not an exclusion)
  • 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
  • PHQ-9 score >15
  • Current pregnancy or plans to become pregnant during study participation
  • Current tobacco use
  • ALT or AST >/= 3 times the upper limit of normal
  • Bicarbonate <18 mmol/L
  • Creatinine > 1.2 mg/dL
  • Any history of seizures
  • Uncontrolled hypertension as determined by the local medical monitor
  • History of structural heart defect or clinically significant arrhythmia
  • Diagnosed monogenic obesity
  • Any history of cholelithiasis
  • Any history of nephrolithiasis
  • Clinically diagnosed hyperthyroidism
  • Untreated thyroid disorder
  • Any disorder, unwillingness, or inability, not covered by any other exclusion criteria, which in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04298203


Contacts
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Contact: Aaron Kelly, PhD 612-626-3402 kelly105@umn.edu
Contact: Claudia Fox, MD 612-301-6616 lusc0001@umn.edu

Locations
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United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Cameron E Naughton, M.P.A.    612-625-3623    naug0009@umn.edu   
Sponsors and Collaborators
University of Minnesota
Investigators
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Principal Investigator: Aaron Kelly, PhD University of Minnesota
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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT04298203    
Other Study ID Numbers: PEDS-2020-28498
First Posted: March 6, 2020    Key Record Dates
Last Update Posted: October 26, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: To be determined

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Minnesota:
Childhood
Adolescent
Additional relevant MeSH terms:
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Obesity
Obesity, Morbid
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Topiramate
Phentermine
Anticonvulsants
Hypoglycemic Agents
Physiological Effects of Drugs
Central Nervous System Stimulants
Appetite Depressants
Anti-Obesity Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action