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

• ClinicalTrials.gov Identifier: NCT05975580
• Recruitment Status: Recruiting
• First Posted: August 4, 2023
• Last Update Posted: September 1, 2023
• Sponsor: University of California, Irvine
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Kishore M Gadde, MD, University of California, Irvine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Obesity	Drug: Topiramate; Drug: Phentermine; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The investigational drugs and placebo capsules will look identical. University of California Irvine Medical Center Investigational Drug Service will dispense the masked study drugs in accordance with randomization. The study statistician who generates the randomization scheme and the research pharmacist who dispenses the study drugs are the only personnel who are unblinded to the randomized assignment. Investigators and all other study personnel and the study subjects will be blinded to the treatment assignment until subjects have completed all visits, all data have been entered, and the data file has been locked.
• Primary Purpose: Treatment
• Official Title: Pharmacotherapy in Conjunction With Lifestyle Counseling for Management of Weight Regain After Bariatric Surgery
• Actual Study Start Date: August 29, 2023
• Estimated Primary Completion Date: April 2, 2027
• Estimated Study Completion Date: July 31, 2027

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Energy intake [ Time Frame: Month 0, Month 12 ]
   Change in energy intake in kcal/d assessed with a dietitian interview. Comparisons between Groups 1, 2, 3 vs placebo.

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Phuong Linh Huynh, MPH; 7144566155; plhuynh@hs.uci.edu

Contact: Qin Wang; qinw15@hs.uci.edu

Locations

United States, California

University of California Irvine Medical Center; Recruiting

Orange, California, United States, 92868

Contact: Phuong Linh Huynh, MPH 714-456-6155 plhuynh@hs.uci.edu

Contact: Qin Wang qinw15@hs.uci.edu

Principal Investigator: Kishore M Gadde, MD

Sponsors and Collaborators

University of California, Irvine

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Kishore M Gadde, MD; University of California, Irvine

More Information

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.

• Responsible Party: Kishore M Gadde, MD, Professor In Residence, Surgery, University of California, Irvine
• ClinicalTrials.gov Identifier: NCT05975580
• Other Study ID Numbers: 1849; R01DK129936 ( U.S. NIH Grant/Contract )
• First Posted: August 4, 2023
• Last Update Posted: September 1, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Kishore M Gadde, MD, University of California, Irvine:

Bariatric surgery; Weight regain; Antiobesity drugs; Treatment of weight regain

Additional relevant MeSH terms:

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