Pharmacotherapy in Conjunction With Lifestyle Counseling for Management of Weight Regain After Bariatric Surgery (PROJECT-BARI)

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity
• Intervention / Treatment: Drug: Topiramate; Drug: Phentermine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Phuong Linh Huynh, MPH; Phone Number: 7144566155; Email: plhuynh@hs.uci.edu
• Study Contact Backup: Name: Qin Wang; Email: qinw15@hs.uci.edu

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • University of California Irvine Medical Center
      • Contact: Qin Wang; Email: qinw15@hs.uci.edu
      • Contact: Phuong Linh Huynh, MPH; Phone Number: 714-456-6155; Email: plhuynh@hs.uci.edu
      • Principal Investigator: Kishore M Gadde, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female subjects aged 18-70 years
2. Had sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) between ≥18 months and ≤10 years ago
3. Weight regain of ≥5% relative to post-surgery nadir weight
4. Body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with weight-related comorbidities
5. 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
6. Must be able to provide written informed consent

Exclusion Criteria:

1. Type 1 diabetes
2. Insulin-dependent type 2 diabetes
3. Fasting plasma glucose (FPG) ≥240 mg/dL
4. 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
5. History of significant (as determined by the investigator) and unstable cardiovascular disease including coronary artery disease, arrhythmias, severe congestive heart failure, or stroke
6. Use of monoamine oxidase inhibitors, current or within 2 weeks
7. Hyperthyroidism or other significant thyroid disease
8. Angle-closure glaucoma
9. Agitated states
10. History of drug abuse within the past year
11. Known hypersensitivity or idiosyncrasy to sympathomimetic amines
12. Severe hepatic disease (non-alcoholic fatty liver disease or non-alcoholic steatohepatitis without portal hypertension or cirrhosis is acceptable)
13. End-stage renal disease
14. History of nephrolithiasis
15. Serum triglycerides ≥500 mg/dL
16. Cancer, not in remission, within the past 2 years except for adequately treated basal cell, squamous cell skin cancer, or in-situ cervical cancer
17. History of psychosis or bipolar disorder
18. Suicidal ideation or unstable/untreated major depressive disorder within the past year
19. Use of antidepressant medication that has not been at stable dose for at least 3 months
20. Hospital Anxiety and Depression Scale (HADS) score of ≥11 for depression or anxiety items
21. Binge Eating Scale (BES) score of ≥27
22. Alcohol use disorder within the past year
23. Epilepsy
24. Currently taking phentermine or topiramate or the combination, or products containing these drugs
25. Currently taking stimulants (e.g., Attention Deficit Hyperactivity Disorder medications)
26. Current use of prescription or over-the-counter weight loss drugs or supplements
27. 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
28. Planning additional bariatric surgery procedures in the next 13 months
29. History of revisional bariatric surgery (revisional surgery after adjustable gastric banding is acceptable)
30. Currently participating in another weight loss program or have plans to participate in the next 13 months
31. Smoking cessation within the previous 3 months or plans to quit smoking in the next 13 months
32. Pregnant or breastfeeding or planning pregnancy in the coming 13 months
33. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Topiramate 50 mg; 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; Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
Experimental: Group B: Topiramate 100 mg; 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; Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
Experimental: Group C: Phentermine 7.5 mg/Topiramate 50 mg; 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; Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate; Drug: Phentermine; Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine
Experimental: Group D: Phentermine 7.5 mg; Phentermine will be started at 7.5 mg daily. Responders at Month 4 will continue the same treatment until Month 12.	Drug: Phentermine; Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine
Experimental: Group E: Phentermine 15 mg; 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; Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine
Experimental: Group F: Phentermine 7.5 mg/Topiramate 50 mg; 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; Topiramate is an anticonvulsant (antiepilepsy) drug. IUPAC ID: 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate; Drug: Phentermine; Phentermine belongs to a class of drugs called anorectics, also known as appetite suppressants. IUPAC name 2-methyl-1-phenylpropan-2-amine
Placebo Comparator: Group P: Placebo; Placebo group will receive placebo.	Drug: Placebo; Placebo is an inactive substance.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grazing	Change in grazing behavior, assessed with the Grazing Questionnaire. Comparisons between Groups 1, 2, 3 vs placebo.	Months 0, 4, 12
Loss-of-control eating	Change in loss-of-control eating, assessed with the Loss-of-Control Eating Scale. Comparisons between Groups 1, 2, 3 vs placebo.	Months 0, 4, 12
Binge eating	Change in binge eating, assessed with the Binge Eating Scale. Comparisons between Groups 1, 2, 3 vs placebo.	Months 0, 4, 12

Collaborators and Investigators

• Sponsor: University of California, Irvine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Kishore M Gadde, MD, University of California, Irvine

Publications and helpful links

General Publications

• Noria SF, Shelby RD, Atkins KD, Nguyen NT, Gadde KM. Weight Regain After Bariatric Surgery: Scope of the Problem, Causes, Prevention, and Treatment. Curr Diab Rep. 2023 Mar;23(3):31-42. doi: 10.1007/s11892-023-01498-z. Epub 2023 Feb 8.

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2023
• Primary Completion (Estimated): April 2, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: July 21, 2023
• First Submitted That Met QC Criteria: August 1, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Bariatric surgery; Antiobesity drugs; Weight regain; Treatment of weight regain
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anticonvulsants; Appetite Depressants; Anti-Obesity Agents; Central Nervous System Stimulants; Sympathomimetics; Topiramate; Phentermine
• Other Study ID Numbers: 1849; R01DK129936 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No