Phentermine/Topiramate in children, adolescents, and young adults with hypothalamic obesity: a pilot and feasibility study

芬特明/托吡酯治疗下丘脑肥胖儿童、青少年和年轻人：一项试点和可行性研究

• 批准号: 10734754
• 负责人: SHANA ERIN MCCORMACK
• 金额: $ 36.17万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734754
• 关键词: Address; Adolescent; Adolescent and Young Adult; Adult; Adverse event; Affect; Age; Agonist; Anxiety; Biological; Body Weight decreased; Body fat; Body mass index; Brain Neoplasms; Cardiometabolic Disease; Caregivers; Case Study; Child; Childhood Brain Neoplasm; Clinical Trials; Cognition; Combined Modality Therapy; Cross-Over Studies; Data; Desire for food; Disease; Dose; Double-Blind Method; Drug usage; Dual-Energy X-Ray Absorptiometry; Eating; Eating Behavior; Energy Metabolism; Epilepsy; Event; Excess Mortality; Excessive Daytime Sleepiness; Exclusion Criteria; FDA approved; Fatigue; Feasibility Studies; Foundations; Froehlich' s Syndrome; Future; GLP-I receptor; Goals; Health; Heterogeneity; Hyperphagia; Hypothalamic Neoplasms; Hypothalamic structure; Impairment; Impulsivity; Individual; Injury; Intervention; Interview; Magnetic Resonance Imaging; Maintenance; Maximum Tolerated Dose; Measures; Metabolic; Mission; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Oral; Outcome; Oxytocin; Participant; Persons; Pharmaceutical Preparations; Phase; Phentermine; Physical activity; Pilot Projects; Placebo Control; Placebos; Pre-Clinical Model; Procedures; Protocols documentation; Randomized; Regulation; Reporting; Research; Resistance; Safety; Sample Size; Sampling; Sequential Multiple Assignment Randomized Trial; Stimulant; Structure; Suggestion; Survivors; Sympathomimetic Amines; Testing; Therapeutic Intervention; Titrations; Visceral fat; Weight Gain; Withdrawal; alertness; arm; attenuation; biomarker identification; capsule; design; dose individualization; exenatide; experience; impression; improved; inclusion criteria; individual response; innovation; metabolic phenotype; metabolic rate; mortality risk; novel therapeutics; obesity treatment; personalized approach; personalized therapeutic; pharmacologic; phase 2 study; pilot trial; placebo controlled trial; prevent; programs; randomized placebo-controlled clinical trial; recruit; response; safety assessment; sibutramine; stimulant use; subcutaneous; success; topiramate; treatment effect; treatment planning; treatment response; treatment strategy; trial design

SUMMARY Hypothalamic obesity (HO) refers to the substantial weight gain that often complicates hypothalamic brain tumors. Children with this treatment-recalcitrant form of obesity have excess rates of metabolic sequelae compared to otherwise healthy children with similar obesity, and later experience excess mortality related to cardiometabolic disease. Our team has made important progress in recent trials. In our 36-week placebo- controlled trial (ECHO, NCT02664441), participants receiving exenatide, a glucagon-like peptide-1 receptor agonist (GLP1RA), demonstrated a larger reduction in body fat than those receiving placebo. While these results are encouraging, in 50% of participants, BMI did not decrease with exenatide, highlighting the need to address treatment non-response. Another pharmacologic option tested by our team is intranasal oxytocin (OXT), which has had success in our case studies and reassuring safety. However, in a recently concluded cross-over study, we observed a nominal, not statistically significant, within-subject weight loss of -0.6 kg attributable to OXT as compared to placebo (NCT02849743), but suggestions of benefit for anxiety and impulsivity. These trials highlight our team's experience and our commitment to developing evidence-supported, individualized approaches to address the problem of treatment non-response in HO. In future, we envision pursuing an innovative sequential multiple assignment randomized trial (SMART) design. A SMART is a multi-staged clinical trial where at each stage, individuals are re-randomized to the next intervention based on accumulated information about response to the previous intervention. HO is particularly suited to a SMART as non-responders may benefit from alternative and/or combination interventions. Moreover, the SMART allows for the identification of biomarkers, such as hypothalamic injury on MRI, to support optimal and efficient treatment planning. In this pilot trial, our objective is to gather key preliminary data about phentermine/topiramate (Ph/T), a promising option containing a sympathomimetic amine (Ph) combined with an appetite-suppressive epilepsy drug (T) that is FDA- approved for “common” obesity but has never been tested in HO. The subset of individuals with HO who experience hyperphagia or excess daytime sleepiness may benefit from the Ph/T-induced decrease in appetite and increase in alertness. We will make preliminary assessments of safety, adverse events and dosing (Aim 1), as well as efficacy (% BMI loss, Aim 2) in a 27-week parallel-arm double-blinded Phase 2 randomized placebo- controlled clinical trial in 12-25-year-old individuals with HO, following the FDA-approved dose titration. We will also measure the proportion of individuals who experience 5% or 2.5% decrease in BMI, explore effects of Ph/T on body fat, eating, autonomic tone, and cognition, and will bank biological samples for future mechanistic analyses. Semi-structured exit interviews with participants and caregivers will help to explain treatment response or non-response, experience of adverse events, and impressions of trial participation. We will next design a SMART to include GLP1RA, Ph/T, and/or other novel therapies like OXT alone and/or in combination for HO.

概括 下丘脑肥胖（HO）是指体重大幅增加，常常使下丘脑复杂化 肿瘤。患有这种顽固性肥胖症的儿童出现代谢后遗症的几率很高 与具有类似肥胖的其他健康儿童相比，后来经历与以下相关的超额死亡率 心脏代谢疾病。我们的团队在最近的试验中取得了重要进展。在我们的 36 周安慰剂中—— 对照试验（ECHO，NCT02664441），参与者接受艾塞那肽（一种胰高血糖素样肽 1 受体） 激动剂（GLP1RA）的身体脂肪比安慰剂组有更大的减少。虽然这些结果 令人鼓舞的是，50% 的参与者的 BMI 并未因艾塞那肽而降低，这凸显了解决这一问题的必要性 治疗无反应。我们团队测试的另一种药理选择是鼻内催产素 (OXT)，它 我们的案例研究取得了成功并保证了安全。然而，在最近结束的一项交叉研究中， 我们观察到，由于 OXT，受试者体内体重减轻了 -0.6 公斤，但没有统计学意义 与安慰剂（NCT02849743）相比，但建议对焦虑和冲动有益。这些试验 强调我们团队的经验以及我们对开发有证据支持的个性化产品的承诺 解决 HO 治疗无反应问题的方法。未来，我们设想追求 创新的序贯多重分配随机试验（SMART）设计。 SMART 是一个多阶段的临床 试验中，在每个阶段，根据累积的结果，将个体重新随机分配到下一个干预措施 有关对先前干预的反应的信息。 HO 特别适合作为无反应者的 SMART 可能受益于替代和/或组合干预措施。此外，SMART 允许识别 生物标志物，例如 MRI 下丘脑损伤，以支持最佳和有效的治疗计划。在这个 试点试验，我们的目标是收集有关芬特明/托吡酯 (Ph/T) 的关键初步数据，这是一个有前途的选择 含有拟交感胺 (Ph) 和 FDA 批准的抑制食欲癫痫药物 (T) 批准用于“常见”肥胖，但从未在 HO 中进行过测试。患有 HO 的个体子集 经历过食欲过盛或白天过度嗜睡可能会受益于 Ph/T 引起的食欲下降 并提高警觉性。我们将对安全性、不良事件和剂量进行初步评估（目标 1）， 以及 27 周平行臂双盲 2 期随机安慰剂试验中的疗效（BMI 损失百分比，目标 2） 在 FDA 批准的剂量滴定后，在 12-25 岁 HO 个体中进行了对照临床试验。我们将 还测量 BMI 下降 5% 或 2.5% 的个体比例，探索 Ph/T 的影响 对身体脂肪、饮食、自主神经张力和认知进行研究，并将为未来的机械学储存生物样本 分析。对参与者和护理人员进行半结构化退出访谈将有助于解释治疗反应 或无反应、不良事件的经历以及参与试验的印象。接下来我们将设计一个 SMART 包括 GLP1RA、Ph/T 和/或其他新颖疗法，例如单独使用 OXT 和/或联合治疗 HO。