SMART Use of Medication for the Treatment ofAdolescent Severe Obesity

在美国，几乎每10个青少年中就有一个患有严重肥胖症(特定年龄和性别的身体质量 体重指数≥是第95个百分位数的1.2倍，或≥35公斤/平方米)，这是一种慢性衰弱疾病。目前的治疗方法 指南要求进行3至6个月的生活方式改变治疗(LSMT)，然后考虑辅助性治疗 单独对LSMT无效的患者的药物治疗。然而，这一武断的时间建议 在开始服药前等待3到6个月并不是有证据的。在做出决定前等待6个月 对于正在努力实现BMI减少的患者来说，改变可能太长了。然而，3个月可能不是 足够长的时间来评估患者对LSMT的反应，因此可能导致过度用药。此外， 没有关于如何管理对一线药物治疗无效的患者的指导意见。 对于成人肥胖症患者，药物治疗通常包括联合用药，如 芬太尼+托吡酯。然而，对于患有严重肥胖症的青少年来说，限制肥胖是不必要的 药物暴露受到高度重视，从一种单一疗法切换到另一种具有不同机制的疗法 作用(例如，从苯丙氨酸改为托吡酯)可能比添加第二种药物更可取 (如芬太尼+托吡酯)。循证治疗指南中的这一差距解决了最佳 辅助药物治疗的时间和顺序很难填补，因为对 LSMT和药物疗法；使用“一刀切”的方法将无法帮助无应答者，并可能 不必要地“过度对待”应答者。相反，适应性干预有可能最大限度地 在限制暴露于无效和/或不必要的药物的风险的同时，为更多的患者提供更好的结果。 具体地说，适应性干预根据反应的预测因素量身定做治疗，然后调整 根据持续的表现随着时间的推移进行治疗。因此，这项临床试验的首要目标是 Garner数据将为开发一种适应性医学干预治疗糖尿病提供信息 严重的青少年肥胖症，包括根据经验得出的决策规则，这些规则解决了 应该开始药物治疗，如果开始药物治疗，最好的顺序是什么 疗程。这项研究将利用序贯多分配随机试验(SMART) 专门为构建适应性干预措施而开发的方法学。150 患有严重肥胖症的青少年(12-18岁)将被招募参加这项分两阶段进行的SMART 系统检查：1)之前对LSMT进行3个月和6个月响应评估的效果 开始辅助药物治疗；2)对于最初的辅助药物治疗无效的患者，其亲属 在苯丙氨酸中加入托吡酯与改用托吡酯单一治疗的疗效比较。全 参与者将接受为期12个月的干预，主要结果将是12岁时BMI的变化 月份。

Nearly 1 out of every 10 adolescents in the U.S. suffers from severe obesity (age- and sex-specific body mass index (BMI) ≥1.2 times the 95th percentile or ≥35 kg/m2), a chronic and debilitating disease. Current treatment guidelines call for 3 to 6 months of lifestyle modification therapy (LSMT) followed by consideration of adjunct pharmacotherapy for patients failing to respond to LSMT alone. However, this arbitrary time recommendation to wait 3 to 6 months before initiating medication is not evidence based. Waiting 6 months before making a change may be too long for patients who are struggling to achieve BMI reduction. Yet, 3 months may not be long enough to assess patient responsiveness to LSMT and could therefor lead to over medication. Further, no guidance exists regarding how to manage patients who are non-responsive to first-line pharmacotherapy. For adults with obesity, treatment with pharmacotherapy routinely includes combination medications, such as phentermine+topiramate. Yet for adolescents with severe obesity, a group for whom limiting unnecessary medication exposure is highly valued, switching from one monotherapy to another with a different mechanism of action (e.g. switching from phentermine to topiramate) may be preferable to adding a second medication (e.g. phentermine+topiramate). This gap in evidence-based treatment guidelines that address the optimal timing and sequence of adjunct pharmacotherapy is difficult to fill because of the response heterogeneity to LSMT and pharmacotherapy; using a “one-size-fits-all” approach will fail to help the non-responders and may unnecessarily “over-treat” the responders. Instead, adaptive interventions have the potential to maximize outcomes for more patients while limiting risk from exposure to ineffective and/or needless medications. Specifically, adaptive interventions tailor therapy according to predictors of response and then adjust the therapy over time based on on-going performance. Thus, the overarching goal of this clinical trial is to garner data that will inform the development of an adaptive medical intervention for the treatment of severe adolescent obesity that includes empirically-derived decision rules that address when adjunct pharmacotherapy should be initiated, and if starting pharmacotherapy, what is the best sequence or course of therapy. This study will utilize a sequential multiple assignment randomized trial (SMART) methodology which was developed specifically for constructing adaptive interventions. One hundred fifty adolescents (age 12-18 years) with severe obesity will be recruited in this 2-staged SMART that will systematically examine: 1) the effect of a 3-month versus 6-month response assessment to LSMT before starting adjunct pharmacotherapy; and 2) for non-responders to initial adjunct phentermine, the relative effectiveness of adding topiramate to phentermine versus switching to topiramate monotherapy. All participants will receive 12 months of intervention and the primary outcome will be change in BMI at 12 months.