Adjunct Phentermine + Topiramate After Bariatric Surgery in 12-24 Year Olds

Study Overview
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Brief Summary
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The goal of this pilot study is to establish the feasibility and initial efficacy of the combination of phentermine and topiramate for adolescents and young adults who require additional risk reduction after bariatric surgery. This study will use a randomized, placebo-controlled, double-blinded design to evaluate an adjunctive 12-week intervention of phentermine + topiramate + standard of care vs. placebos + standard of care 6 months after bariatric surgery, among 12 to 24 year olds who don't achieve expected weight loss or who remain severely obese (n=10 total).

Official Title
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Adjunctive Anti-Obesity Pharmacotherapy in Adolescents and Young Adults After Bariatric Surgery: A Randomized Controlled Pilot Study

Conditions
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Obesity, Morbid, Bariatric Surgery, Adolescent, Young Adult, Drug Therapy

Intervention / Treatment
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* Drug: Phentermine
* Drug: Immediate Release Topiramate
* Drug: Placebo for Phentermine
* Drug: Placebo for Immediate Release Topiramate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Status post sleeve gastrectomy or roux-en-y gastric bypass At 6 months after bariatric surgery, has not achieved >= 26% decrease in weight from preoperative weight (within 1 week of surgery) OR remains severely obese (>=120% of 95th%ile or BMI >=35kg/m2 for 12-17yo; BMI >=35kg/m2 for 18-24yo) Exclusion Criteria: Absolute contraindication to phentermine or topiramate (i.e. phentermine: history of coronary artery disease, stroke, arrhythmia, congestive heart failure, uncontrolled hypertension), hypersensitivity to sympathomimetic amines, current or recent (within 14 days) use of monoamine oxidase inhibitors, glaucoma, or hyperthyroidism; topiramate: hypersensitivity to topiramate, history of nephrolithiasis) Concomitant use of phenytoin, carbamazepine, or carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide, or dichlorphenamide) Use of anti-obesity medication within 6 months of screening Initiation of a new medication associated with weight loss or gain within 30 days of screening Type 2 diabetes mellitus Hypothalamic obesity Unmanaged (e.g. without medications and/or psychotherapy) clinically significant (determined by a mental health professional using diagnostic instruments and/or clinical interview) depression or anxiety History of any suicidal behavior within 30 days of screening or any suicidal ideation with either some intent to act or with intent and a specific plan within 30 days of screening History of schizophrenia Severe hepatic impairment (ALT >10x upper limit of normal or known synthetic liver dysfunction) Moderate or severe renal impairment (GFR <30mL/min/1.73m2) Dosage change to hypertension, dyslipidemia, depression, or anxiety medication <4 weeks prior to study enrollment Contraception started <7 days prior to study enrollment Current pregnancy/plans to become pregnant within 16 weeks from study drug start date Females without a long acting reversible contraceptive (LARC) who do not commit to using 2 forms of birth control

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two-arm parallel assignment where the experimental arm will receive active drugs + standard of care and the control arm will receive placebo drugs + standard of care.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phentermine & Topiramate<br>Phentermine- Formulation: 8mg scored tablet, Dosage/Frequency/Duration: 4mg x 7d then 8mg x 7d then 12mg x 7d then 16mg x 63d, taken once every morning + Immediate release topiramate- Formulation: 25mg tablet, Dosage/Frequency/Duration: 25mg x 7d then 50mg x 7d then 75mg x 7d then 100mg x 63d then 50mg x 7 days then 25mg x 7d, taken once every morning + Standard of Care (multidisciplinary postoperative bariatric surgery clinic visits) | Drug: Phentermine<br>* Phentermine tablet<br>* Other names: 2-methyl-1-phenylpropan-2-amine;Drug: Immediate Release Topiramate<br>* Topiramate tablet<br>* Other names: [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydrodi[1,3]dioxolo[4,5-a:5',3'-d]pyran-3a-yl]methyl sulfamate;|
| Placebo Comparator: Placebo Drugs<br>Placebo Phentermine- Formulation: 8mg scored tablet, Dosage/Frequency/Duration: 4mg x 7d then 8mg x 7d then 12mg x 7d then 16mg x 63d, taken once every morning + Placebo Immediate release topiramate- Formulation: 25mg tablet, Dosage/Frequency/Duration: 25mg x 7d then 50mg x 7d then 75mg x 7d then 100mg x 63d then 50mg x 7 days then 25mg x 7d, taken once every morning + Standard of Care (multidisciplinary postoperative bariatric surgery clinic visits) | Drug: Placebo for Phentermine<br>* Compounded tablet to mimic phentermine 8mg tablet<br>Drug: Placebo for Immediate Release Topiramate<br>* Compounded tablet to mimic immediate release topiramate 25mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Enrollment Rate | Number enrolled divided by number eligible | 24 months | 
| Dropout Rate | Number who do not complete the study divided by number enrolled | 24 months | 
| Adherence to Study Drugs | Percentage of missed doses (pill count); Presence/Absence of amphetamine in the urine | 12 weeks | 
| Frequency of drug-related adverse events | Count and description of adverse events possibly or definitely related to the study drugs. Elicited using a standardized checklist during 3 study phone calls and 3 in-person study visits, laboratory monitoring of serum bicarbonate, and comprehensive review of systems, vitals, physical exam, and mood/suicidality assessment using validated instruments at every study visit. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent weight change | (Baseline weight - Weight at 12 weeks)/Baseline weight x 100 | Baseline and 12 weeks | 
| Percent BMI change | (Baseline BMI - BMI at 12 weeks)/Baseline BMI x 100 | Baseline and 12 weeks | 
| Change in BMI percent of the 95th%ile | (Baseline BMI % of the 95th%ile - BMI % of the 95th%ile at 12 weeks) | Baseline and 12 weeks | 
| Change in heart rate | (Heart rate at baseline - Heart rate at 12 weeks) | Baseline and 12 weeks | 
| Change in systolic blood pressure | Systolic blood pressure at baseline - Systolic blood pressure at 12 weeks | Baseline and 12 weeks | 
| Change in diastolic blood pressure | Diastolic blood pressure at baseline - Diastolic blood pressure at 12 weeks | Baseline and 12 weeks | 
| Change in total cholesterol (mg/dL) | Total cholesterol at baseline - Total cholesterol at 12 weeks | Baseline and 12 weeks | 
| Change in triglycerides (mg/dL) | Triglycerides at baseline - Triglycerides at 12 weeks | Baseline and 12 weeks | 
| Change in LDL cholesterol (mg/dL) | LDL at baseline - LDL at 12 weeks | Baseline and 12 weeks | 
| Change in HDL cholesterol (mg/dL) | HDL at baseline - HDL at 12 weeks | Baseline and 12 weeks | 
| Change in alanine aminotransferase (ALT) (U/L) | ALT at baseline - ALT at 12 weeks | Baseline and 12 weeks | 
| Change in hemoglobin A1c (HbA1c) (%) | HbA1c at baseline - HbA1c at 12 weeks | Baseline and 12 weeks | 
| Change in % fat mass | % Fat mass at baseline - %Fat mass at 12 weeks measured by DEXA | Baseline and 12 weeks | 
| Change in resting metabolic rate (RMR) | RMR at baseline - RMR at 12 weeks measured by indirect calorimetry | Baseline and 12 weeks | 
| Change in Dietary Intake | The adolescent/young adult will complete a dietary record on 3 consecutive days (2 weekdays, 1 weekend day) based on standardized protocols for dietary assessment. Total caloric intake, macronutrient, and micronutrient breakdown will be assessed. | Baseline and 12 weeks | 
| Change in Hunger | The adolescent/young adult will report hunger before each meal and snack for 24 hours using a 100mm visual analogue scale (0= no hunger, 100 = most hunger) | Baseline and 12 weeks | 
| Change in Satiety | The adolescent/young adult will report satiety before each meal and snack for 24 hours using a 100mm visual analogue scale (0= no fullness, 100= most full) | Baseline and 12 weeks | 
| Change in Eating in the Absence of Hunger | Validated questionnaire: Eating in the Absence of Hunger-Parent (EAH-P) completed by the parent/guardian about their adolescent/young adult. This measure has 14 items. Each item is on a 5-point Likert scale ranging from 1= never to 5= always. A higher score indicates more eating in the absence of hunger. Total and sub scales are calculated by taking the average of the items. Total score measures the overall construct Eating in the Absence of Hunger Subscales include: External Cues (4 items); Response to negative affect (6 items); Fatigue/Boredom (4 items). | Baseline and 12 weeks | 
| Change in Cognitive Restraint, Disinhibited Eating, and Predisposition to Hunger | The Three-Factor Eating Questionnaire will be completed by the adolescent/young adult. This is a 51-item measure that is divided into 2 parts, and assesses 3 eating behaviors: 1) Cognitive Dietary Restraint (20 items), 2) Disinhibited Eating (16 items), and 3) Predisposition to hunger (15 items). Higher scores in each domain indicate more of each of those behaviors. The minimum score for factors 1, 2, and 3 are: 0, 0, and 0. The maximum score for factors 1, 2, and 3 are: 20, 16, and 15 Part I includes items 1-36 rated as either True (1) or False (0) Part II includes items 37-51 and is rated on a 4-point Likert-like scale with one exception- item 50 is rated on a 6-point scale. Scores for each of the three eating behaviors are calculated by taking the average of the items, and are most commonly reported separately, not as a total score. | Baseline and 12 weeks | 
| Change in Weight Related Quality of Life- Adolescent | Impact of Weight on Quality of Life-Kids questionnaire will be completed by the adolescents age <=19. Total and each of the 4 sub scales (Physical Comfort-6 items, Body Esteem-9 items, Social Life-6 items, and Family Relations-6 items) range from a minimum score of 0 to a maximum of 100. Higher scores indicate higher quality of life. | Baseline and 12 weeks | 
| Change in Weight Related Quality of Life- Parent | Impact of Weight on Quality of Life-Kids Parent Proxy questionnaire will be completed by the parent of the adolescent/young adult. Total and each of the 4 sub scales (Physical Comfort-6 items, Body Esteem-9 items, Social Life-6 items, and Family Relations-6 items) range from a minimum score of 0 to a maximum of 100. Higher scores indicate higher quality of life. | Baseline and 12 weeks | 
| Change in Weight Related Quality of Life- Young adult | Impact of Weight on Quality of Life-Lite questionnaire will be completed by the young adult age >=20. Total and each of the 5 sub scales (Physical function-11 items, Self Esteem-7 items, Sexual Life-4 items, Public distress-5 items, and Work-4 items) range from a minimum score of 0 to a maximum of 100. Higher scores indicate higher quality of life. | Baseline and 12 weeks | 
| Change in General Health Related Quality of Life: PedsQL instrument | PedsQL instrument will be completed by the adolescent/young adult. There are 4 scales: Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items) and 3 Summary Scores: Total Scale Score (23 items), Physical Health Summary Score (8 items), and Psychosocial Health Summary Score (15 items). Items are rated on a 0-4 scale. Items are reverse scored and linearly transformed to a 0-100 scale, such that 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicated better health-related quality of life. Scale Scores are calculated as the sum of the items over the number of items answered. Psychosocial Health Summary Score is calculated as the sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales. Physical Health Summary Score is the same as the Physical Functioning Scale Score. | Baseline and 12 weeks | 
| Change in Depression | The adolescent/young adult will complete the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Each item is rated on a 0 to 3 scale (positive items are reverse scored). Minimum score is 0 and maximum is 60. Higher scores indicate more depressive symptoms. Total score is calculated by summing each of the 20 individual items scores. | Baseline and 12 weeks | 
| Participant Satisfaction: questionnaire | The participating family will be asked to complete a satisfaction questionnaire that will assess reasons for participation, experience during study visits, satisfaction with the effect of the study drug, ease of communication with study staff, and study burden. | At 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pilot, Feasibility, Initial Efficacy, Randomized Controlled Trial