Pharmacotherapy in Conjunction With Lifestyle Counseling for Management of Weight Regain After Bariatric Surgery

Study Overview
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Brief Summary
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This is a randomized controlled trial employing a Sequential Multiple Assignment Randomized Trial (SMART) design to test whether pharmacotherapy, in conjunction with lifestyle counseling, can reverse weight regain after bariatric surgery.

Detailed Description
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Although bariatric surgery is the most effective treatment for severe obesity, a large proportion of patients experience significant weight regain with longer follow-up. In this randomized controlled trial employing a SMART design, a total of 120 subjects with weight regain after bariatric surgery, will be initially randomized in a 3:3:2 ratio to daily treatment with topiramate (TPM) 50 mg or phentermine (PHEN) 7.5 mg or placebo. After 4 months, responders (those with ≥5% weight loss) will continue the same treatment, while nonresponders will be re-randomized to a higher dose of the same drug or phentermine/topiramate 7.5/50 mg combination (PHEN/TPM) during Months 5-12. All subjects will receive diet and lifestyle counseling throughout the study. Aim 1: To determine whether pharmacotherapy can reverse post-bariatric surgery weight regain. Hypothesis: Compared to placebo, all three active drug therapies - TPM, PHEN, and PHEN/TPM will lead to greater percent weight loss at Month 12. Aim 2: To examine change in energy intake assessed by a dietitian interview. Hypothesis: Compared to placebo, active drug therapies will lead to greater reduction in energy intake at Month 12. Aim 3: To examine changes in the most common maladaptive eating behaviors in the post-bariatric surgery patients - grazing, loss-of-control eating, and binge eating. Hypothesis: Compared to placebo, active drug therapies will lead to decreased maladaptive eating behaviors.

Official Title
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Pharmacotherapy in Conjunction With Lifestyle Counseling for Management of Weight Regain After Bariatric Surgery

Conditions
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Obesity

Intervention / Treatment
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* Drug: Topiramate
* Drug: Phentermine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged 18-70 years Had sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) between ≥18 months and ≤10 years ago Weight regain of ≥5% relative to post-surgery nadir weight Body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with weight-related comorbidities Women of childbearing potential must be using appropriate contraception to avoid pregnancy throughout the study, and must have a negative pregnancy test at study entry Must be able to provide written informed consent Exclusion Criteria: Type 1 diabetes Insulin-dependent type 2 diabetes Fasting plasma glucose (FPG) ≥240 mg/dL Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥100 mm Hg on the average of three seated measurements after being at rest for at least 5 minutes History of significant (as determined by the investigator) and unstable cardiovascular disease including coronary artery disease, arrhythmias, severe congestive heart failure, or stroke Use of monoamine oxidase inhibitors, current or within 2 weeks Hyperthyroidism or other significant thyroid disease Angle-closure glaucoma Agitated states History of drug abuse within the past year Known hypersensitivity or idiosyncrasy to sympathomimetic amines Severe hepatic disease (non-alcoholic fatty liver disease or non-alcoholic steatohepatitis without portal hypertension or cirrhosis is acceptable) End-stage renal disease History of nephrolithiasis Serum triglycerides ≥500 mg/dL Cancer, not in remission, within the past 2 years except for adequately treated basal cell, squamous cell skin cancer, or in-situ cervical cancer History of psychosis or bipolar disorder Suicidal ideation or unstable/untreated major depressive disorder within the past year Use of antidepressant medication that has not been at stable dose for at least 3 months Hospital Anxiety and Depression Scale (HADS) score of ≥11 for depression or anxiety items Binge Eating Scale (BES) score of ≥27 Alcohol use disorder within the past year Epilepsy Currently taking phentermine or topiramate or the combination, or products containing these drugs Currently taking stimulants (e.g., Attention Deficit Hyperactivity Disorder medications) Current use of prescription or over-the-counter weight loss drugs or supplements Taking prescription or over-the-counter drugs or products, which in the opinion of the PI, could be associated with significant effects on body weight Planning additional bariatric surgery procedures in the next 13 months History of revisional bariatric surgery (revisional surgery after adjustable gastric banding is acceptable) Currently participating in another weight loss program or have plans to participate in the next 13 months Smoking cessation within the previous 3 months or plans to quit smoking in the next 13 months Pregnant or breastfeeding or planning pregnancy in the coming 13 months History of, or any existing condition that, in the opinion of the Principal Investigator, would interfere with the study outcomes or place the subject at unacceptable risk by participating in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Interventional Model Description: A total of 120 eligible subjects, with weight regain after bariatric surgery, will be initially randomized in a 3:3:2 ratio to daily treatment with topiramate (TPM) 50 mg or phentermine (PHEN) 7.5 mg or placebo. After 4 months, responders (those with ≥5% weight loss) will continue the same treatment, while nonresponders will be re-randomized to a higher dose of the same drug or phentermine/topiramate 7.5/50 mg combination (PHEN/TPM) during Months 5-12. All randomized subjects will receive lifestyle counseling throughout the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Topiramate 50 mg<br>Topiramate will be started at 25 mg daily and the dose will be increased to 50 mg daily after 15 days. Responders at Month 4 will continue the same treatment until Month 12. | Drug: Topiramate<br>* Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate<br>|
| Experimental: Group B: Topiramate 100 mg<br>Nonresponders in the topiramate group at Month 4 will be re-randomized in a 1:1 ratio to receive topiramate 100 mg or phentermine/topiramate 7.5/50 mg during Months 5-12. | Drug: Topiramate<br>* Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate<br>|
| Experimental: Group C: Phentermine 7.5 mg/Topiramate 50 mg<br>Nonresponders in the topiramate group at Month 4 will be re-randomized in a 1:1 ratio to receive topiramate 100 mg or phentermine/topiramate 7.5/50 mg during Months 5-12. | Drug: Topiramate<br>* Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate<br>Drug: Phentermine<br>* Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine<br>|
| Experimental: Group D: Phentermine 7.5 mg<br>Phentermine will be started at 7.5 mg daily. Responders at Month 4 will continue the same treatment until Month 12. | Drug: Phentermine<br>* Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine<br>|
| Experimental: Group E: Phentermine 15 mg<br>Nonresponders in the phentermine group at Month 4 will be re-randomized in a 1:1 ratio to receive phentermine 15 mg or phentermine/topiramate 7.5/50 mg during Months 5-12. | Drug: Phentermine<br>* Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine<br>|
| Experimental: Group F: Phentermine 7.5 mg/Topiramate 50 mg<br>Nonresponders in the phentermine group at Month 4 will be re-randomized in a 1:1 ratio to receive phentermine 15 mg or phentermine/topiramate 7.5/50 mg during Months 5-12. For Group F, topiramate will be dosed at 25 mg daily for the 15 days in Month 5 and 50 mg daily thereafter, | Drug: Topiramate<br>* Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate<br>Drug: Phentermine<br>* Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine<br>|
| Placebo Comparator: Group P: Placebo<br>Placebo group will receive placebo. | Drug: Placebo<br>* Placebo is an inactive substance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent weight loss at Month 12 - Topiramate vs placebo | Topiramate (Group 1 [Group A + Group B]) vs placebo (Group P) | Month 0, Month 12 | 
| Percent weight loss at Month 12 - Phentermine vs placebo | Phentermine (Group 2 [Group D + Group E) vs placebo (Group P) | Month 0, Month 12 | 
| Percent weight loss at Month 12 - Phentermine/Topiramate | Phentermine/Topiramate (Group 3 [Group C + Group F]) vs placebo (Group P) | Month 0, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Energy intake | Change in energy intake in kcal/d assessed with a dietitian interview. Comparisons between Groups 1, 2, 3 vs placebo. | Month 0, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bariatric surgery, Weight regain, Antiobesity drugs, Treatment of weight regain