Project Summary
Although bariatric surgery is the most effective treatment for severe obesity, a large proportion of patients
experience significant weight regain with longer follow-up. Because weight regain is associated with re-
emergence of weight-related comorbidities, increased health care costs, and impaired quality of life, it is
imperative to effectively manage this problem. Diet, exercise, and behavior therapy have demonstrated
minimal efficacy in reversing weight regain. Pharmacotherapy could be useful to manage this clinical problem.
However, there are no published randomized controlled trials (RCTs) of pharmacotherapy for reversal of
weight regain. This is a major therapeutic gap, which the proposed project will aim to fill. In this well-powered
meticulously designed double-blind RCT employing a Sequential Multiple Assignment Randomized Trial
(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. The placebo group will receive placebo for the full 12 months. All subjects
will receive diet and lifestyle counseling throughout the study. Aim 1. To determine whether pharmacotherapy
can reverse post-bariatric surgery weight regain. We hypothesize that, 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 objectively assessed with the Intake-Balance Method using doubly labeled
water and DXA. We hypothesize that active drug therapy 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. We hypothesize that, compared to placebo,
all three drug therapies will lead to decreased maladaptive eating behaviors. A battery of carefully chosen
exploratory outcomes including other likely modulators of changes in energy balance (appetite, night eating
behavior, dietary restraint, thyroid hormones, leptin, and physical activity), additional efficacy (ALT, AST,
glycemia, lipid levels, inflammatory markers, quality of life, and psychological wellbeing), and safety (heart rate,
BP, anxiety, depressive symptoms) will be investigated. Additional efficacy questions including the best initial
treatment, dose escalation vs combination strategy, and each adaptive intervention will be examined. The
findings of this highly rigorous study will provide high-quality evidence for the efficacy and safety of
pharmacotherapy in reversing weight regain after bariatric surgery. Study results could lead to a change in
clinical practice paradigms and enhance long-term outcomes for patients after bariatric surgery. Because the
SMART design mimics clinical practice, the findings of this RCT are directly translatable to clinical practice.
