Pharmacotherapy in conjunction with lifestyle counseling for management of weight regain after bariatric surgery (PROJECT-BARI)

项目摘要 虽然减肥手术是治疗严重肥胖症最有效的方法，但很大一部分患者 随着随访时间的延长，体重明显反弹。因为体重反弹与再- 出现体重相关的合并症，增加医疗保健费用，降低生活质量， 必须有效地解决这个问题。饮食锻炼和行为疗法已经证明 逆转体重反弹的效果微乎其微。药物治疗可能有助于解决这一临床问题。 然而，目前还没有发表的关于药物治疗逆转 体重恢复这是一个主要的治疗空白，拟议的项目将致力于填补这一空白。在这个强大的 精心设计的双盲随机对照试验，采用序贯多重分配随机试验 （SMART）设计，共120例减肥手术后体重恢复的受试者，最初将随机分配至 托吡酯（TPM）50 mg或芬特明（PHEN）7.5 mg或安慰剂的每日治疗比例为3：3：2。经过4 月，应答者（体重减轻≥5%的患者）将继续相同的治疗，而无应答者将 被重新随机分配至更高剂量的相同药物或芬特明/托吡酯7.5/50 mg组合 (PHEN/TPM）。安慰剂组将接受安慰剂治疗整整12个月。所有受试者 在整个研究过程中将接受饮食和生活方式咨询。目标1。为了确定药物治疗是否 可以逆转减肥手术后的体重反弹。我们假设，与安慰剂相比， 药物治疗- TPM、PHEN和PHEN/TPM在第12个月时将导致更大的体重减轻百分比。目标2.到 使用双标记的摄入平衡法客观评估能量摄入的变化 水和DXA。我们假设，积极的药物治疗将导致更大的减少能量摄入， 第12个月。目标3。为了检查肥胖后最常见的适应不良饮食行为的变化， 手术病人--吃草、饮食失控和暴食。我们假设，与安慰剂相比， 所有这三种药物疗法都将导致适应不良饮食行为的减少。一组精心挑选的 探索性结果，包括能量平衡变化的其他可能调节剂（食欲、夜间进食 行为、饮食限制、甲状腺激素、瘦素和体力活动），额外的功效（ALT，AST， 血脂水平、炎症标志物、生活质量和心理健康）和安全性（心率， 血压、焦虑、抑郁症状）。其他疗效问题，包括最佳初始 将检查治疗、剂量递增与联合策略以及每种适应性干预。的 这项高度严格的研究的结果将为有效性和安全性提供高质量的证据。 药物治疗逆转减肥手术后体重反弹。研究结果可能会导致 临床实践范例，并提高减肥手术后患者的长期结局。因为 SMART设计模拟临床实践，该RCT的结果可直接转化为临床实践。

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.